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International Journal of Impotence Research (2008) 20, 479–486& 2008 Nature Publishing Group All rights reserved ORIGINAL ARTICLERandomized, double-blind, placebo-controlled study ofpostoperative nightly sildenafil citrate for the prevention of erectiledysfunction after bilateral nerve-sparing radical prostatectomy H Padma-Nathan1, AR McCullough2, LA Levine3, LI Lipshultz4, R Siegel5,9, F Montorsi6, F Giuliano7and G Brock8, on behalf of the Study Group10 1Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 2Department of Urology, New York University School of Medicine, New York University Medical Center, New York, NY,USA; 3Department of Urology, Rush Medical College, Rush University, Chicago, IL, USA; 4Scott Department of Urology,Baylor College of Medicine, Houston, TX, USA; 5Sexual Health Team, Pfizer Inc, New York, NY, USA; 6Department ofUrology, University Vita Salute San Raffaele, Milan, Italy; 7Department of Physical Medicine and Rehabilitation, RaymondPoincare´ Hospital, Garches, France and 8Department of Urology, University of Western Ontario, London, ON, Canada Four weeks after bilateral nerve-sparing radical retropubic prostatectomy, men with normalerectile function before surgery were randomized to double-blind sildenafil (50 or 100 mg) orplacebo nightly for 36 weeks, followed by an 8-week drug-free period before assessment of erectilefunction. Enrollment was prematurely ceased and only 76 men completed because, assuming aplacebo response rate similar to the published literature (for example, 34% in meta-analysis), the25% response at blinded interim review suggested a lack of treatment effect. On the contrary,spontaneous erectile function (a combined score of X8 for questions 3 and 4 of the InternationalIndex of Erectile Function and a positive response to ‘Were erections good enough for satisfactorysexual activity?’) occurred in only 4% of the placebo group (n ¼ 1 of 25) versus 27% (n ¼ 14 of 51,P ¼ 0.0156, Fisher’s exact test) of the sildenafil group. Nightly sildenafil administration for 36 weeksafter surgery markedly increased the return of normal spontaneous erections.
International Journal of Impotence Research (2008) 20, 479–486; published online 24 July 2008 Keywords: prostatectomy; erectile dysfunction; sildenafil citrate factors, such as the age of the patient, preoperativeerectile function and the experience of the surgeon.
Erectile dysfunction (ED) after bilateral nerve-spar- Anatomically, the small size of the cavernous nerves ing radical prostatectomy may be related to multiple precludes clear visualization during surgery, makingthem susceptible to intraoperative trauma anddamage.Even spared nerves can experience neur-apraxia, a temporary failure in nerve conductionresulting from insult. Neurapraxia may explain temporary (short-term) ED following nerve-sparing University School of Medicine, New York University prostatectomy. Sustained ED is more likely to Medical Center, 540 1st Avenue, Sirball Building, Suite10U, New York, NY 10016, USA.
be caused by secondary cavernosal trabecular smooth muscle apoptosis and its replacement with 9R Siegel was an employee of Pfizer at the time of this Post-prostatectomy ED is severe and may include 10The other members of the Study Group are Professor loss of nocturnal erections, and recovery is slower Robert Andrianne, Belgium; David Bell, Canada; Gregory than generally reported in the literature; many men Broderick, USA; Serge Carrier, Canada; Professor Beatrice will not regain erectile function for more than 12 Cuzin, France; Harry Jeoffrey Deeths, USA; Wayne months.ED after prostatectomy is generally treated Hellstrom, USA; Sender Herschorn, Canada; Ronald W symptomatically, as needed when intercourse is Lewis, USA; Raymond C Rosen, USA; Ridwan Shabsigh, anticipatHowever, early regular use of intra- USA; Phillip Stricker, Australia.
Received 25 March 2007; revised 23 May 2008; accepted cavernosal alprostadil injections, in an uncontrolled 23 May 2008; published online 24 July 2008 study, has been shown to improve the recovery rate Sildenafil and ED after radical prostatectomy of spontaneous erections after nerve-sparing radical 50- or 100-mg sildenafil, or matching placebo, was retropubic prostatectomy.Despite this benefit, taken once daily at nighttime. Erectile function was pain, complications and inconvenience detract from assessed, and plethysmography was conducted in the willingness of patients to use intracavernosal the subgroup, after 12, 24 and 36 weeks of treatment.
When double-blind treatment was discontinued, Early, regular (every other night) use of sildenafil patients remained untreated for 8 weeks (phase 3); citrate (Viagra; Pfizer Inc, New York, NY, USA) after no ED therapy, including sildenafil, was permitted.
nerve-sparing radical retropubic prostatectomy has At the end of this period, erectile function, and been shown, in an uncontrolled human study, to nocturnal penile tumescence and rigidity in the preserve or increase intracorporeal smooth muscle content.Moreover, sildenafil taken at bedtime has Computer-generated randomization was in a 1:1:1 been shown to significantly improve nocturnal ratio using the method of random permuted blocks erectile activity in men with vasculogenic or and a pseudorandom number generator. Eligible patients were allocated a randomization number mediated by release of cavernous nerve nitric oxide at the first visit of phase 2. Tablets containing during rapid eye movement and phase 4 sleep.
50- or 100-mg sildenafil or matching placebo were Indeed, since the inception of the current study, it supplied to the investigators in blister cards in a has become common clinical practice to provide sildenafil postoperatively for variable periods of Institutional Review Board/independent Ethics time. For example, in a study of 167 men who were Committee approval was obtained at all study sites, potent before bilateral nerve-sparing radical retropubic and signed informed consent was obtained from all prostatectomy, approximately half used sildenafil on an on-demand basis as needed for the symptomatictreatment of ED; recently reported 4-year follow-updata from this study have shown a continuing improvement in erectile function with time.
Eligible men were 18–70 years of age, weighing The current study provides, for the first time, 50–125 kg, and scheduled to undergo bilateral objective data and a protocol for the use of sildenafil nerve-sparing radical retropubic prostatectomy by after nerve-sparing prostatectomy. The objective was experienced surgeons. Patients had to have normal to evaluate the efficacy of prophylactic, nightly use preoperative erectile function, wish to return to of sildenafil in preventing long-term ED. A second sexual activity after surgery and be in a stable, objective was to investigate the potential mechan- heterosexual relationship for the past 6 months.
ism of action of sildenafil in preventing long-term Normal preoperative erectile function was defined ED by evaluating its effects on nocturnal penile as a combined score of at least 8 on questions 3 and 4 of the International Index of Erectile Function (Q3:‘Over the past 4 weeks, when you attempted sexualintercourse, how often were you able to penetrateyour partner?’; Q4: ‘Over the past 4 weeks, during sexual intercourse, how often were you able tomaintain your erection after you had penetrated your partner?’). Individual scores for these questions This study was designed to be a randomized, were 0 (‘Did not attempt intercourse’), 1 (‘Almost never/never’), 2 (‘A few times (much less than half fixed-dose, multicenter study conducted in three the time)’), 3 (‘Sometimes (about half the time)’), 4 phases between April 1999 and October 2001 at (‘Most times (much more than half the time)’) and 5 outpatient urology clinics. A total of 16 sites in North America, France, Belgium and Australia For the subgroup undergoing plethysmography, screened patients, and 11 sites in North America an additional inclusion criterion was normal penile and France enrolled and randomized patients.
tumescence and rigidity, defined as X55% base During the 1- to 4-week preoperative assessment rigidity for 10 consecutive minutes on at least 1 of 2 (phase 1), all patients underwent baseline evalua- consecutive nights of monitoring before surgery.
tion of their erectile function using the International Patients were excluded if they had pathological Index of Erectile FuncA subgroup, consisting stage greater than PT2, a tumor Gleason score equal to of all men enrolled at two sites, also underwent or greater than 8 on a preoperative biopsy, prostate- evaluation of nocturnal penile tumescence and specific antigen levels equal to or greater than rigidity at home (2 consecutive nights) using penile 20 mg lÀ1, positive lymph nodes or required post- plethysmography (RigiScan; Timm Medical Tech- operative radiation or androgen ablation therapy.
nologies, Eden Prairie, MN, USA). At 4 weeks after Patients were also excluded if they had a sleep surgery, patients entered the 36-week double-blind, disorder, were taking sedative/hypnotics as sleep aids postoperative treatment (phase 2) during which or were receiving nitrates or any treatment for ED.
International Journal of Impotence Research
Sildenafil and ED after radical prostatectomyH Padma-Nathan et al expected based on rates of spontaneous recovery of The primary measure was the percentage of patients erectile function reported in the published litera- ture.After enrollment ceased, two US study definition was established a priori as those patients centers remained active to complete all the study who, at the end of phase 3, had a combined score of visits in the ongoing patients in the plethysmogra- at least 8 for Q3 and Q4 of the International Index phy subgroup and to provide information to aid in of Erectile Function, and also answered ‘yes’ to the question, ‘Over the past 4 weeks, have your All statistical analyses were performed using erections been good enough for satisfactory sexual Statistical Analysis System software version 6.12 for efficacy analyses and version 8.2 for demo- Secondary measures were changes from baseline graphic and safety analyses. Primary and secondary in the six-item Erectile Function domain of the efficacy variables were analyzed in patients who International Index of Erectile Function and, for completed the 36-week double-blind treatment the plethysmography subgroup, the duration of period and the 8-week drug-free evaluation period.
penile tumescence and rigidity. The Erectile Function In the original statistical analysis plan, the primary domain has a score range of 1–30, with ED graded as efficacy measure (percentage of responders) was severe (1–10), moderate (11–16), mild to moderate to be analyzed using the pair-wise Cochran– (17–21), mild (22–25) and none (26–30).
Mantel–Haenszel (CMH) test. However, becausethe Mantel–Fleiss criterion was not satisfied, theCMH test was determined to be inappropriate foranalysis purposes. Therefore, Fisher’s exact test (two-tailed) was used as an alternative (and appro- On the basis of analyses of Q3 and Q4 of the priate for the existing number of patients) approach, International Index of Erectile Function in previous with the Bonferroni adjustment to account for studies, a conservative standard deviation of 2.00 multiple comparisons with placebo. Secondary was assumed. If the mean sildenafil versus placebo efficacy measures were analyzed using the nonpara- difference for at least one of the sildenafil groups metric Wilcoxon rank-sum test. Safety was assessed was 1.5 points for both variables, then a sample size in patients who took at least one dose of study of 44 patients per treatment group would provide 90% power to detect a significant differencebetween variables singly and 80% power to detectsignificant differences for both variables jointly,based on two-sided analysis of variance tests conducted at the 0.05 significance level withDunnett’s adjustment. Assuming that 80% of rando- Of 238 patients screened, 125 were randomized to mized patients would contribute to the intent-to-treat treatment and 123 received at least one dose of study analyses, a sample size of 55 patients per treatment drug. In total, 94% (117 of 125) of the randomized group was required. However, enrollment ceased patients were enrolled at five North American sites.
after 125 because an interim blinded review of data Patients were largely similar among treatment from the 35 completed patients showed a response rate of only 25% (9 of 35), which was not what was Across the groups, a similar number of patients Table 1 Demographics of the patients who took study medication and of the analyzed population Took study medication (n ¼ 123)/analyzed (n ¼ 76) aOne additional patient was randomized to this group, but discontinued before receiving study drug.
International Journal of Impotence Research
Sildenafil and ED after radical prostatectomy had concomitant hypertension (n ¼ 10–12), hyper- Response rate after 36 weeks on study drug and 8 lipidemia (n ¼ 10–11) and ischemic heart disease (n ¼ 1–2). All patients had good erectile functionat screening and developed ED as a result of The 36-week double-blind treatment period was completed by 82 men. The subsequent 8-week drug-free evaluation period was completed by 76 men, who constituted the population analyzed for efficacy: placebo, n ¼ 25; sildenafil 50 mg, n ¼ 23; sildenafil 100 mg, n ¼ 28. Of these 76 men, 54 were enrolled at the two US study centers, whichremained active to complete all the study visits in aDefined as those who scored X8 on Q3 and Q4 of the ongoing patients, and were included in the plethys- International Index of Erectile Function and also answered ‘yes’ to the question ‘Over the past 4 weeks, have your erections been good enrolled at three other North American study enough for satisfactory sexual activity?’ centers. The eight men randomized at the other six P ¼ 0.02 versus placebo (two-tailed Fisher’s exact test).
study centers were discontinued prematurely when P ¼ 0.04 versus placebo (two-tailed Fisher’s exact test).
the centers were terminated after the interim review.
P ¼ 0.03 versus placebo (two-tailed Fisher’s exact test).
Reasons for the 47 premature discontinuations inthe placebo, sildenafil 50-mg, and sildenafil 100-mgtreatment groups, respectively, were lack of efficacy treatment were 26.9±2.2 (27), including 26.3±1.9 (n ¼ 3, 2 and 1); adverse events (n ¼ 1, 5 and 1); loss (27) in the 50-mg group and 27.3±2.5 (28) in the to follow-up, withdrawn consent, noncompliance, 100-mg group; for the one patient who responded to loss of stable sexual partner or protocol violation (n ¼ 7, 2 and 6) and study closure (n ¼ 6, 8 and 5).
Demographics were largely similar among treatmentgroups in the analyzed population, and between the Secondary efficacy results: nocturnal penile rigidity analyzed population and the larger population of Of the 54 men who underwent RigiScan assessment, 35 were randomized to sildenafil treatment. Prior tosurgery, nocturnal penile rigidity at the base of thepenis was similar between sildenafil responders Primary efficacy results: percentage of responders (n ¼ 10) and nonresponders (n ¼ 25); (median: 59 At 48 weeks after undergoing prostatectomy (that is, and 65 min, respectively). Median duration of 8 weeks after discontinuation of drug treatment), 15 nocturnal penile rigidity was markedly reduced to of 76 patients were categorized as responders (20%), less than 1 min in both sildenafil responders and including 6 of 23 in the sildenafil 50 mg group nonresponders, 4 weeks post-surgery. At 48 weeks (26%), 8 of 28 in the sildenafil 100 mg group (29%) after prostatectomy, and 8 weeks after discontinua- and 1 of 25 in the placebo group (4%); overall, 14 of tion of drug treatment, sildenafil responders had a 51 patients who completed sildenafil treatment longer duration of base rigidity (median: 6 min) than patients treated with sildenafil had a combinedscore of at least 4 for Q3 and Q4 of the InternationalIndex of Erectile Function, indicating that partial Nightly use of sildenafil was well tolerated The most commonly reported adverse events weredyspepsia, headache, flushing, abnormal vision and Secondary efficacy results: erectile function domain rhinitis. Most adverse events were transient and Erectile Function domain scores were reported as mild in nature; two patients in the 50-mg sildenafil mean±s.d. (median). Before surgery, scores were group discontinued because of treatment-related 28.8±1.6 (30) in the sildenafil group and 28.6±2.2 adverse events. Although six serious adverse events (30) in the placebo group, indicating no ED. End- were reported, none of these were related to study of-study scores were 13.1±9.5 (9) in the men who had used sildenafil during the treatment phase,including 12.4±9.2 (9) in the 50-mg group and13.7±9.8 (10) in the 100-mg group, compared with 8.8±7.0 (6), in those who had used placebo duringthe treatment phase. More importantly, the end- In a small but representative sample, we have demon- of-study scores for the responders to sildenafil strated that nightly administration of sildenafil International Journal of Impotence Research
Sildenafil and ED after radical prostatectomyH Padma-Nathan et al Erectile Function domain scores and by nocturnal penile plethysmography. The similar response rate between the 50- and 100-mg doses of sildenafil suggests future study to identify the minimally The study results reveal that the majority of men who undergo bilateral nerve-sparing radical retro- pubic prostatectomy have ED a year later. Because we assumed a placebo response rate similar to that of the published literature (see below), the low overall response rate (25% (9 of 35)) at the blinded interim review suggested a lack of treatment effect and resulted in a decision to prematurely cease enrollment. Most discontinuations were because of study closure (n ¼ 19). Although prematurely ceas-ing enrollment and closing study sites precluded Figure 1 Nocturnal penile rigidity at the base of the penis asassessed using RigiScan, in responders (n ¼ 10) and nonrespon- achieving the original sample size goal, the treat- ders (n ¼ 25) to sildenafil treatment, before and 4 and 48 weeks ment assignment followed the original randomiza- after prostatectomy. Responders were a priori defined as those tion ratio. Given the ultimate number of patients, patients who, at the end of the 8-week drug-free period, had a use of Fisher’s exact test (two-tailed), with the combined score of at least 8 on Q3 and Q4 from the International Bonferroni adjustment to account for multiple Index of Erectile Function (scores for each question ranged from 0to 5) and answered ‘yes’ to the question ‘Over the past 4 weeks, comparisons with placebo, was an appropriate have your erections been good enough for satisfactory sexual alternative statistical test to the originally planned activity?’ Data are shown as median and 25th to 75th percentile statistical analysis. However, the results should be bars, with 10th and 90th percentile limits. Of the 54 men who interpreted in the context of patients actually underwent RigiScan assessment, 19 others were randomized toplacebo.
Nightly sildenafil was well tolerated: only two patients, both in the sildenafil 50-mg group, dis- continued the study because of adverse eventsrelated to sildenafil treatment. Six patients discon- tinued prematurely because of lack of efficacy, suggesting a misunderstanding of the study objec-tive: the prevention of long-term ED following The 4% rate of return for spontaneous erectile function in the placebo group (n ¼ 1 of 25) is considerably lower than was expected based on the published literature. There is a wide range of rates reported in the literature, with the variation Most commonly occurring AEs (X2% of patients) being attributed to patient age, preoperative sexual function, time since surgery, nerve-sparing procedure, example, in two large series of preoperatively potent men who underwent nerve-sparing prostatectomy (most frequently bilateral nerve-sparing), recovery oferections occurred in approximately two-thirds (571 of 858and 342 of 503the recovery rate aNone of the serious AEs were considered treatment related.
was inversely related to age at surgery. In contrast, in bThe only treatment-related AEs that were associated with patient a series of 1072 Medicare patients, mostly consisting discontinuation were mild fatigue, headache and dyspepsia in of older patients with lower rates of preoperative one patient treated with sildenafil 50 mg, and mild dyspepsia andsevere headache in a second patient treated with sildenafil 50 mg.
potency, only 11% had erections sufficient forintercourse following surgeryIn a meta-analysisof 14 studies conducted through 2001, including for 9 months, beginning 1 month after bilateral over 600 patients, the probability of maintaining erectile function was 34% (95% confidence interval resulted in the return of spontaneous erections in (CI) 30–38%) within the year following nerve- 27% (n ¼ 14 of 51) of men, compared with only 4% sparing prostatectomy.The discrepancy between (n ¼ 1 of 25) of men receiving placebo. These results the published literature and the results of the were observed at the end of an 8-week drug-free current study may reflect differences from our period (1 year post-surgery) and were supported by methodology, such as the absence of controls to International Journal of Impotence Research
Sildenafil and ED after radical prostatectomy prevent bias, the use of nonvalidated questionnaires or a less stringent definition of responders. For compromising the endothelium-dependent and neu- example, in other studies the criteria for a positive rogenic relaxation of corpus cavernosum smooth response are often not well defined, lack details (that is, on the quality of erections (full versus increasing synthesis of transforming growth factor- partial rigidity)) and do not necessarily correspond b and endothelin, which ultimately leads to vaso- to the ability to achieve sexual intercourse.
constriction and corporeal fibrosisSildenafil In contrast to the published literature, we used a selectively inhibits phosphodiesterase type 5 and stringent definition of response. The requirement for thereby prevents cGMP degradation,compensat- a combined score of at least 8 for Q3 (‘When you ing for the reduced availability of nitric oxide during attempted sexual intercourse, how often were you hypoxia; this enhances smooth muscle relaxation of able to penetrate your partner?’) and Q4 (‘During the corpus cavernosum,promoting blood flow to sexual intercourse, how often were you able to maintain your erection after you had penetrated Sildenafil may have unique and more relevant your partner?’) necessitated a response of ‘Almost mechanisms of action in preventing long-term ED always/always’ on Q3 and ‘Sometimes (about half after nerve-sparing prostatectomy. In patients with the time)’ on Q4 or a response of ‘Most times (much chronic heart failure, in whom vascular endothelial more than half the time)’ on each question. Penetra- function (vasodilation) is impaired, administration tion and maintained erection are clinically mean- of sildenafil improved endothelium-dependent va- ingful to the patient because they are prerequisite to sodilation, as demonstrated by improved flow- satisfactory sexual intercourse. In addition, we mediated vasodilation compared with placebo.
required an answer of ‘yes’ to the question, ‘Over Similarly, in patients with type 2 diabetes, low-dose the past 4 weeks, have your erections been good sildenafil improved vascular endothelial function.
enough for satisfactory sexual activity?’ This strin- Also, phosphodiesterase 5 inhibitors have been gent definition of response was attained by 27% (14 shown to be neuroprotective to cultured spinal motor and nonmotor neurons,and sildenafil Because it is now common clinical practice to increased neurogenesis and reduced neurological provide sildenafil on an on-demand basis for deficits in rats treated within 24 h of strokeThus, variable periods of time after prostatectomy as therapeutic postoperative intervention with silde- needed for the symptomatic treatment of ED, recent nafil may improve corpus cavernosum endothelial reports of post-prostatectomy potency often reflect function and promote recovery of nerve function.
this practice pattern. For example, approximatelyhalf of 167 men who were potent before bilateralnerve-sparing radical retropubic prostatectomy used sildenafil on-demand; recovery of normal erections, Even with nerve-sparing surgery, most men will defined as a score of at least 26 on the Erectile have severe ED a year after prostatectomy, strongly Function domain of the International Index of suggesting the need for early primary prevention Erectile Function, was achieved by 8% of patients measures. This is the first long-term, prospective, after 12 months, compared with 51% after 48 blinded study that assessed prophylactic nightly months.An on-demand study of sildenafil after dosing of sildenafil on recovery of erectile function nerve-sparing radical retropubic prostatectomy has after bilateral nerve-sparing radical retropubic pros- demonstrated that treatment satisfaction peaked tatectomy. The failure to complete the study accord- between 18 and 24 months.These results suggest ing to its initial power calculations, which were that further study is needed to determine the based on anticipated placebo response rates that did optimum timing and duration of sildenafil therapy.
not hold true, does not negate the importance of the The mechanism of action of sildenafil in prevent- findings. Nightly administration of sildenafil for 36 ing long-term ED following bilateral nerve-sparing weeks beginning 4 weeks after prostatectomy re- radical retropubic prostatectomy remains unclear sulted in a marked restorative effect (an increase but is probably multifactorial. This is in keeping over placebo in ability to achieve spontaneous with the apparently multifactorial etiology of ED erection) 8 weeks after the end of sildenafil treat- after prostatectomy, in which vascular factors ment. These results show that pharmacological appear to be important in some cases and neuro- intervention during the convalescent period can genic factors apparently play a major role.This enhance the recovery of spontaneous erections, and study clearly demonstrates the profound loss of provide objective data and a protocol for the now nocturnal erections after surgery. Hypoxia may be common clinical practice of providing sildenafil involved in both temporary and permanent ED postoperatively for variable periods of time.
following prostatectomy. Hypoxia causes temporary Prior to surgery, patients should be counseled ED by significantly reducing the synthesis and about the realistic outcome and educated about the release of nitric oxide (the principal mediator of most effective treatment alternatives available to penile erection via the nitric oxide/cyclic guanosine optimize the return of erectile function after surgery.
International Journal of Impotence Research
Sildenafil and ED after radical prostatectomyH Padma-Nathan et al These data suggest that there is an advantage in initiating early primary prevention measures afterbilateral nerve-sparing radical retropubic prostatect- 1 McCullough AR. Prevention and management of erectile omy, and that more men may regain spontaneous dysfunction following radical prostatectomy. Urol Clin North erectile function when treated proactively with 2 Walsh PC, Partin AW, Epstein JI. Cancer control and quality of sildenafil. Follow-up studies are warranted to life following anatomical radical retropubic prostatectomy: support the results of the current study and to results at 10 years. J Urol 1994; 152: 1831–1836.
examine the effect of lower doses, earlier initiation 3 Klein LT, Miller MI, Buttyan R, Raffo AJ, Burchard M, of therapy and intermittent therapy, and to deter- Devris G et al. Apoptosis in the rat penis after penile mine the optimal duration of therapy. Other unan- denervation. J Urol 1997; 158: 626–630.
4 User HM, Hairston JH, Zelner DJ, McKenna KE, McVary KT.
swered questions include the mechanism of action Penile weight and cell subtype specific changes in a post- of sildenafil in preserving erectile function and radical prostatectomy model of erectile dysfunction. J Urol whether sildenafil use results in better return of function, faster return of function or both.
5 Zippe CD, Raina R, Thukral M, Lakin MM, Klein EA, Agarwal A.
prostatectomy. Curr Urol Rep 2001; 2: 495–503.
6 Meuleman EJ, Mulders PF. Erectile function after radical prostatectomy: a review. Eur Urol 2003; 43: 95–102.
7 Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri L et al. Recovery of spontaneous erectile function This study was funded by Pfizer Inc. Editorial after nerve-sparing radical retropubic prostatectomy with and assistance was provided by Deborah M Campoli- Richards of Complete Healthcare Communications, results of a prospective, randomized trial. J Urol 1997; 158: 8 Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical retropubic prosta- tectomy. J Urol 2004; 171: 771–774.
9 Montorsi F, Maga T, Strambi LF, Salonia A, Barbieri L, Scattoni V Gerald Brock: Consultant, investigator for clinical et al. Sildenafil taken at bedtime significantly increases research, and speakers bureau member for Pfizer nocturnal erections: results of a placebo-controlled study.
Inc, Lilly-ICOS, Bayer, GSK, Johnson & Johnson, 10 Rabbani F, Patel M, Scardino PT. Time course of recovery of potency after bilateral nerve sparing radical prostatectomy.
Francois Giuliano: Investigator for clinical and preclinical research, meeting lecturer, and member 11 Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, of advisory board for Pfizer Inc, Bayer-GSK, Lilly- Mishra A. The International Index of Erectile Function (IIEF): ICOS, Johnson & Johnson; preclinical research for a multidimensional scale for assessment of erectile dysfunc- Solvay Pharmaceuticals, Roche; investigator for 12 Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH.
preclinical research and meeting lecturer for Sanofi- Diagnostic evaluation of the erectile function domain of the International Index of Erectile function. Urology 1999; 54: Larry Levine: Consultant for Pfizer Inc, Lilly- ICOS, Auxillium, Johnson & Johnson; investigator 13 Hong EK, Lepor H, McCullough AR. Time dependent patient for clinical research for Pfizer Inc, Bayer-GSK, satisfaction with sildenafil for erectile dysfunction (ED)after nerve-sparing radical retropubic prostatectomy (RRP).
Auxillium; lecturer for Pfizer Inc, Lilly-ICOS, Int J Impot Res 1999; 11: S15–S22.
14 Catalona WJ, Ramos CG, Carvalhal GF. Contemporary results Larry Lipshultz: Consultant for Pfizer Inc, Lilly- of anatomic radical prostatectomy. CA Cancer J Clin 1999; 49: ICOS, Auxillium, and Solvay Pharmaceuticals; investigator for clinical research for Pfizer Inc and 15 Catalona WJ, Carvalhal GF, Mager DE, Smith DS. Potency, continence and complication rates in 1870 consecutive radical retropubic prostatectomies. J Urol 1999; 162: 433–438.
Andrew McCullough: Consultant for Pfizer Inc, 16 Fowler Jr FJ, Barry MJ, Lu-Yao G, Wasson J, Roman A, Lilly-ICOS, Auxillium, Johnson & Johnson; investi- Wennberg J. Effect of radical prostatectomy for prostate cancer gator for clinical research for Pfizer Inc, Lilly-ICOS, on patient quality of life: results from a Medicare survey.
Bayer-GSK, Guilford Pharmaceuticals, Ion Channel, 17 Robinson JW, Moritz S, Fung T. Meta-analysis of rates of Johnson & Johnson and Schering Plough; advisory erectile function after treatment of localized prostate carcino- board and lecturer for Pfizer Inc, Lilly-ICOS and ma. Int J Radiat Oncol Biol Phys 2002; 54: 1063–1068.
18 Dubbelman YD, Dohle GR, Schroder FH. Sexual function before and after radical retropubic prostatectomy: a systematicreview of prognostic indicators for a successful outcome. Eur Medical System, Bayer-GSK, Johnson & Johnson, 19 Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J.
Harin Padma-Nathan: Consultant, received grant Nitric oxide and cyclic GMP formation upon electrical field support (for this and other clinical trials) from, and stimulation cause relaxation of corpus cavernosum smooth participated in CME educational program for Pfizer muscle. Biochem Biophys Res Commun 1990; 170: 843–850.
20 Bush PA, Aronson WJ, Buga GM, Rajfer J, Ignarro LJ. Nitric Inc, Lilly-ICOS, Bayer-GSK, NexMed and Palatin oxide is a potent relaxant of human and rabbit corpus cavernosum. J Urol 1992; 147: 1650–1655.
International Journal of Impotence Research
Sildenafil and ED after radical prostatectomy 21 Azadzoi KM, Kim N, Brown ML, Goldstein I, Cohen RA, 26 Katz SD. Potential role of type 5 phosphodiesterase inhibition Saenz de Tejada I. Endothelium-derived nitric oxide and in the treatment of congestive heart failure. Congest Heart Fail smooth muscle tone. J Urol 1992; 147: 220–225.
27 Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S.
22 Kim N, Vardi Y, Padma-Nathan H, Daley J, Goldstein I, Saenz de Tejada I. Oxygen tension regulates the nitric oxide pathway.
Physiological role in penile erection. J Clin Invest 1993; 91: patients with chronic heart failure. J Am Coll Cardiol 2000; 23 Moreland RB. Is there a role of hypoxemia in penile fibrosis: a 28 Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA.
viewpoint presented to the Society for the Study of Impotence.
Acute and prolonged effects of sildenafil on brachial artery Int J Impot Res 1998; 10: 113–120.
flow-mediated dilatation in type 2 diabetes. Diabetes Care 24 Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM et al. Sildenafil: an orally active type 5 cyclic 29 Nakamizo T, Kawamata J, Yoshida K, Kawai Y, Kanki R, GMP-specific phosphodiesterase inhibitor for the treatment of Sawada H et al. Phosphodiesterase inhibitors are neuropro- penile erectile dysfunction. Int J Impot Res 1996; 8: 47–52.
tective to cultured spinal motor neurons. J Neurosci Res 2003; 25 Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effects of sildenafil on the relaxation of human corpus 30 Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M et al.
cavernosum tissue in vitro and on the activities of cyclic Sildenafil (Viagra) induces neurogenesis and promotes nucleotide phosphodiesterase isozymes. J Urol 1998; 159: functional recovery after stroke in rats. Stroke 2002; 33: International Journal of Impotence Research

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must contact Horizon directly. This will enable Horizon to better answer your questions and service you in the event that you may need any assistance. For questions or assistance, please direct your email to productsupport@horizonhobby.com, or call 877.504.0233 toll free to speak to a service technician. Inspection or Repairs If this Product needs to be inspected or repaired, please call for a

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Guidelines on Handling Chemical Carcinogens, Teratogens and Mutagens 1995 New Edition incorporating requirements of CoSHH 1994 1. Background, Scope and Purpose of the Code The Control of Substances Hazardous to Health Regulations 1994 (section 7)introduced specific legal duties relating to the use of carcinogens, including a hierarchyof precautions which are MANDATORY . In addition the Ap

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