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From the * South Orange County Medical Research
Center, Laguna Woods, California; the CT
Clinical Research Center, Waterbury, Connecticut;
California Professional Research, Newport
Beach, California; Aurora Urology, Aurora,
Colorado; || Eli Lilly and Company, Indianapolis,
Indiana; and ¶ ZymoGenetics Inc, Seattle,
Washington.
| Correspondence to: Dr Jay M. Young, South Orange County Medical Research Center, 24301 Paseo de Valencia, Suite 100; Laguna Woods, CA 92653 (e-mail: jyoung20{at}cox.net). |
| Received for publication August 4, 2004; accepted for publication November 16, 2004. |
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Abstract |
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Key words: Phosphodiesterase inhibitors, efficacy, successful sexual intercourse, Sexual Encounter Profile (SEP) diary
The introduction of sildenafil citrate marked the beginning of oral phosphodiesterase type 5 (PDE5) inhibitors as a treatment for ED. PDE5 inhibitors have been shown to enhance erectile response in patients with ED by mediating the relaxation of the vascular smooth muscle of the penis (Ballard et al, 1998; Angulo et al, 2001). In response to sexual stimulation, nitric oxide (NO) is released from nonadrenergic, noncholinergic neurons in the penis and from the endothelial cells lining the penile vasculature (Saenz de Tejada et al, 1988; Ignarro et al, 1990; Rajfer et al, 1992; Traish et al, 2000). Released NO induces an increase in cyclic guanosine monophosphate (cGMP) levels in penile vascular smooth muscle cells, causing dilatation of the penile arteries and accumulation of blood in the cavernosal tissue, ultimately resulting in erection (Carvajal et al, 2000). PDE5 enzyme causes the breakdown of cGMP, enhancing detumescence.
Tadalafil (Cialis®; Lilly ICOS LLC, Bothell, Wash and Indianapolis, Ind) is a selective and potent inhibitor of PDE5 that has been approved by the Federal Drug Administration for the treatment of ED in the United States. In primary phase 3 studies, tadalafil at 10- and 20-mg doses was consistently superior to placebo and showed a statistically significant, robust improvement on all primary efficacy endpoints (Erectile Function [EF] domain score of the International Index of Erectile Function [IIEF], Sexual Encounter Profile [SEP] Question 2, and SEP3) (Brock et al, 2002; Lilly ICOS LLC, 2003; Carson et al, 2004). Furthermore, an integrated analysis of the primary efficacy and safety studies showed that 20-mg tadalafil improved erections in 81% of patients with ED, compared with 35% of placebo-treated patients (Brock et al, 2002).
Tadalafil has a unique pharmacokinetic profile with a mean terminal half-life of 17.5 hours (Patterson et al, 2001; Lilly ICOS LLC, 2003). This pharmacokinetic profile suggests that tadalafil may be effective for a long period of time. In a clinical study in an at-home setting, tadalafil at a dose of 20 mg was shown to significantly improve patients' ability to complete successful sexual intercourse up to 36 hours postdose, compared to placebo-treated patients (Porst et al, 2003). Additionally, a significantly higher percentage of patients on tadalafil 10 mg were able to achieve an erection 24 hours after dosing, compared to patients taking placebo, as assessed by RigiScan® (Dacomed Corporation, Minneapolis, Minn) evaluations (Padma-Nathan et al, 2001).
This phase 3 study was designed to further evaluate the effectiveness of 20-mg doses of tadalafil (Porst, 2003), and to assess for the first time the effectiveness of 10-mg tadalafil vs placebo, in improving the success of sexual attempts made at the preassigned times of 24 or 36 hours after dosing. Three main differences in the protocol design, compared to the study of Porst et al (2003), are as follows: 1) the addition of an equilibration phase with dosing as needed, to offer patients the advantage to learn how to properly use the medication before being restricted to a prespecified time window during the assessment phase; 2) the addition of 2 extra doses of study medication for each time point during the assessment phase (4 vs 2 doses); and 3) the use of a parallel design vs a cross-over design with regard to the assigned time points. The study was carried out in men with mild to severe ED.
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Materials and Methods |
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The study consisted of a 4-week run-in phase without medication, to
establish baseline severity of ED; a 2- to 4-week equilibration phase with
dosing as needed before sexual activity, to develop familiarity with the use
of the study medication; a 4- to 6-week assessment phase, to determine the
efficacy at 24 and 36 hours following dosing; and a 6-month open-label active
medication extension phase
(Figure). Results from the
open-label extension phase are not included in this report. During the run-in
phase, patients who met the inclusion/exclusion criteria for enrollment were
stratified into mild (17 to 30), moderate (11 to 16), and severe (
10) ED
groups according to their self-reported baseline EF domain scores on the IIEF
questionnaire. Although EF domain scores of greater than or equal to 26 are
indicative of normal erectile function, patients who initiated the study with
scores within this range (26 through 30) were included in the study on an
intent-to-treat basis and were randomized to the mild group (17 to 30) for
classification purposes. Twenty-two patients (4.6% of enrolled men) had an EF
domain score of greater than or equal to 26 at baseline and were randomized to
placebo (N = 10), tadalafil 10 mg (N = 4), or tadalafil 20 mg (N = 8).
Patients were randomly assigned within each severity group into 6 possible
groups in a 1:1:1:1:1:1 ratio. That is, there was one group for each of the 6
combinations of assigned time (24 or 36 hours) and treatment (placebo,
tadalafil 10 mg, or tadalafil 20 mg). Randomization was performed so that ED
severity would be balanced across the 6 groups. The allocation to
assigned-time groups was open label but was not revealed to patients and
onsite personnel until the initiation of the assessment phase. During the
equilibration phase, patients were given a supply of study medication to take
as needed up to once daily at any time before expected sexual activity. The
purpose of the equilibration phase was to provide an opportunity for the
patients to learn how to use the study medication when sexual activity was not
constrained to a specific time postdose. During the assessment phase, patients
were asked to take 4 doses of study medication, each dose separated by at
least 7 days, and each followed by a sexual attempt at the preassigned time
after dosing (24 or 36 hours). Additionally, the first dose of study
medication during the assessment phase and the last dose of study medication
in the equilibration phase were to be separated by at least 7 days. After the
initial attempt was made at the assigned time, the subject was free to make
additional sexual attempts before the next dose of study medication.
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Patient Population
This multicenter phase 3 study enrolled 483 patients with ED across 38
clinical sites in the United States. Men who were at least 18 years of age and
who reported a minimum of a 3-month history of ED were eligible to enroll in
this study. These patients were to report on their sexual attempts with the
same adult female partner.
Patients were excluded from the study if they met any of the exclusion criteria specified in the protocol. These criteria included clinically significant penile deformities or penile implants; a recent history of stroke or spinal cord trauma; unstable cardiovascular status (eg, unstable angina, myocardial infarction, or myocardial revascularization within the prior 90 days); use of nitrates, cancer chemotherapy, or antiandrogens; or failure to achieve any erection following radical prostatectomy or pelvic surgery. Additionally, patients who had previously received sildenafil citrate treatment that, in the opinion of the study investigator, had been ineffective were not eligible to enroll in the study. No other approved or experimental medications or treatments or devices to treat ED were allowed during the study. Men with ED due to untreated hypogonadism were excluded from the clinical trial. Twenty-two patients received concomitant testosterone treatment during the postbaseline period. Compliance with the study medication and dosing schedule was assessed at each patient visit throughout the duration of the study. Patients who were significantly noncompliant were discontinued from the study, including those patients who, in the opinion of the investigator, repeatedly failed to comply with the time constraints required between dosing and sexual attempts made during the assessment phase. Only intercourse attempts that fell within the specified time-point windows of 24 hours (22 to 26 hours) or 36 hours (33 to 39 hours) postdose were included in the analysis.
Efficacy Measures
Assessments of individual sexual attempts were obtained through responses
to SEP diaries. Patients were asked to record the outcome of each sexual
attempt both during the treatment-free run-in phase and following treatment
during the equilibration and assessment phases. The primary efficacy variable
used to assess the effectiveness of tadalafil for sexual attempts made 24 or
36 hours after dosing was the proportion of "yes" responses to
SEP3 ("Did your erection last long enough for you to have successful
intercourse?" [yes/no]). Only patients with at least one postbaseline
evaluable attempt were included in the analysis. By definition, a postbaseline
evaluable attempt met the following criteria: 1) represented the first attempt
after a treatment dose, 2) occurred within the subject's assigned-time window
postdose, and 3) had SEP diary data recorded for it. Only attempts during the
assessment phase of the study were assessed as evaluable or nonevaluable.
Secondary efficacy variables included the percentage of "yes" responses to SEP questions 1 (ability to achieve at least some erection), 2 (ability to insert penis into partner's vagina), 4 (satisfaction with the hardness of erection), and 5 (overall satisfaction with the sexual experience).
Safety
Safety was assessed through evaluation of incidence of all reported adverse
events (AEs) and any changes in vital signs (blood pressure and pulse).
Treatment-emergent adverse events (TEAEs) reported by patients were recorded
throughout the study, at each clinic visit, and were defined as events that
first occurred or worsened after baseline randomization. The safety outcome
measure was the incidence of TEAEs by treatment group (placebo or tadalafil 10
or 20 mg) without regard to the assigned time. Additionally, physical
examinations were performed at the screening and last study visits to the
clinic before the start of the open-label extension phase. All concomitant
medications taken during the study were recorded at every visit.
Statistical Analyses
The primary efficacy variable was the mean change from baseline to endpoint
during the assessment phase, in the per-patient percentage of
"yes" responses to SEP3. For each assigned time in sequence,
inferences regarding change from baseline to assessment phase in SEP3 were
based on an analysis of covariance (ANCOVA) model that included terms for the
baseline value of the efficacy variable (SEP3 score), treatment group
(placebo, tadalafil 10 mg, or tadalafil 20 mg), pooled site, and (if
significant at P < .10) the baseline-by–treatment group
interaction. The analysis of safety included all enrolled patients. Analyses
of TEAEs used the Fisher exact test.
Primary and secondary analyses were done on a modified intent-to-treat (ITT) basis. The modified ITT analysis included all "ITT evaluable patients," that is, patients with at least one baseline observation and one evaluable postbaseline observation. An evaluable attempt was defined as a sexual attempt that 1) was the first attempt after a treatment dose, 2) occurred within the subject's assigned-time window postdose, and 3) had SEP diary data recorded for it. Only attempts during the assessment phase of the study were assessed as evaluable or nonevaluable. Only those attempts that fell within the assigned-time window were included in the analysis. For the 24-hour assigned time, a window of 22 to 26 hours was allowed. For the 36-hour assigned time, a window of 33 to 39 hours was allowed. For each SEP question, the baseline and postbaseline scores were the patient's percentage of "yes" responses relative to the number of sexual encounters during the run-in and treatment (assessment) periods, respectively.
Unless otherwise specified, hypothesis tests were 2-sided, with a significance level of .05. Primary efficacy comparisons of 10- and 20-mg doses with placebo were adjusted using the method of Dunnett. To protect against type I error when testing multiple primary hypotheses, within each dose, each assigned-time hypothesis was tested in a sequential fashion and appropriately adjusted for multiple-dose comparisons. The evaluation of efficacy at 24 hours for a particular dose preceded the evaluation of efficacy at 36 hours for the same dose. Type I error was split between the two doses using Dunnett multiple-comparison adjustments.
Additional Efficacy Analyses
The percentages of "yes" responses to SEP questions 1, 2, 4,
and 5 were tabulated by group (eg, treatment and assigned time). The same
ANCOVA model was fitted for these variables as for the primary efficacy
variable. No adjustments were made for multiple comparisons.
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Results |
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Efficacy
Tadalafil at 20- and 10-mg doses was superior to placebo in the percentage
of successful intercourse attempts at either 24 hours (P = .038 and
<.001 for 10 and 20 mg, respectively) or 36 hours (P < .001 for
both doses) after dosing, as measured by patient responses to SEP3
(Table 2).
Table 2 summarizes the mean
per-patient change in percentages of "yes" responses to SEP3
during the assessment phase (endpoint) from the run-in phase (baseline) for
ITT evaluable patients for the 24- and 36-hour assigned times, respectively.
The mean per-patient percentages of sexual intercourse attempts at 24 hours
that were successful on 20- and 10-mg tadalafil were 67.3% and 55.8%,
respectively, compared with 41.8% on placebo. The mean per-patient percentages
of sexual intercourse attempts at 36 hours that were successful on 20- and
10-mg tadalafil were 61.9% and 56.2%, respectively, compared with 32.8% on
placebo (Table 2). Similar
results were obtained when patients who reported an IIEF score of greater than
or equal to 26 at baseline were excluded from the analysis (data not
shown).
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On average, across all treatment groups, 84%, 77.4%, 71.2%, and 56% of patients had at least 1, 2, 3, or 4 evaluable attempts, respectively, at the 24-hour assigned time. Eighty-six percent (86.3%), 81.7%, 73.3%, and 55.8% of patients had at least 1, 2, 3, or 4 evaluable attempts, respectively, at the 36-hour assigned time. For the 24-hour assigned window, the mean time from dosing to evaluable attempt was 24.3 hours in both the placebo and 20-mg tadalafil groups, and this value was 24.4 hours in the 10-mg tadalafil group. For the 36-hour assigned window, the mean time from dosing to evaluable attempt was 36.2 hours in both the placebo and 10-mg tadalafil groups and was 36.3 hours in the 20-mg tadalafil group.
The effectiveness of tadalafil in improving the success of sexual attempts made 24 or 36 hours after dosing was demonstrated in patients with ED regardless of their baseline ED severity (Table 3). The mean per-patient percentages of successful sexual intercourse attempts at endpoint at 24 hours for the 20-mg tadalafil group for severe, moderate, or mild ED patients were 41.7%, 85.9%, and 77.4%, respectively; and for the 10-mg tadalafil group, these values were 34.5%, 54.2%, and 72.2%, compared to 19.6%, 42.9%, and 58.3% in patients with severe, moderate, or mild ED who were taking a placebo (Table 3). Similar results were observed in mean per-patient percentages of successful sexual attempts at 36 hours among patients with mild through severe ED at baseline. Patients on 20-mg tadalafil reported endpoint SEP3 scores of 43.2%, 57.8%, and 75.7% in the severe, moderate, or mild ED groups, respectively; patients on 10-mg tadalafil scored 33.3%, 60.9%, and 68.1%, compared to 17.4%, 20.5%, and 50.0% in patients taking the placebo (Table 3). Some of the tadalafil treatment groups did not meet statistical significance for change from baseline compared to placebo (based on ED severity) at 24 hours (P = .147, .149, and .135 for 10-mg mild, moderate, and severe ED groups, respectively) and 36 hours (P = .061 and .085 for 10-mg severe and 20-mg moderate ED groups, respectively), likely because of the small sample size included in these analyses (Table 3).
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Tadalafil was statistically significantly superior to placebo on all secondary measures of efficacy, with the exception of SEP2 for the tadalafil 10-mg group at 24 hours postdose (P = .119 vs placebo; Table 4). Two patients in the placebo group (during the equilibration phase) and 1 patient in the tadalafil 20-mg group (during the assessment phase) discontinued the study because of lack of efficacy (patient perception).
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Safety
Treatment with tadalafil was well tolerated, and TEAEs were generally mild
or moderate in severity. The most common TEAEs (
2% in any tadalafil
treatment group) were headache, back pain, dyspepsia, nasopharyngitis, nasal
congestion, upper respiratory tract infection, myalgia, and influenza
(Table 5). The only TEAEs for
which the difference in incidence between placebo and tadalafil (10 and 20 mg
combined) was statistically significant were headache (P < .001),
back pain (P = .024), and nasal congestion (P = .048;
Table 5). The incidence of
these 3 events was higher in the tadalafil groups than in the placebo group.
No clinically significant changes in vital signs were observed.
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Twenty-three patients (4.8% of enrolled patients) across all treatment groups were discontinued as a result of a protocol violation that consisted, in the majority of cases, of failure to have any evaluable sexual attempt during the treatment period. Of the 5 patients taking tadalafil (1% of enrolled men) who withdrew because of nonserious adverse events (all considered possibly related to the study medication by the investigator), 2 patients (1 each in the 10- and 20-mg tadalafil groups) experienced headache; 1 patient in the 20-mg tadalafil group experienced dyspepsia; and 1 each in the 10-mg tadalafil group experienced back pain or testicular swelling. One patient (0.2% of enrolled men) with a history of hypertension, diabetes, and smoking died after randomization to 20-mg tadalafil as a result of acute myocardial infarction, which the investigator considered unrelated to the study medication or protocol procedures. Two other serious adverse events (unrelated to the study medication) occurred in the placebo group. The discontinuation rates due to AEs were 0.6% and 1.8% in the placebo and tadalafil groups, respectively.
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Discussion |
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h to less than or equal to 1 h; greater than 1 to less
than or equal to 4 h; greater than 4 to less than or equal to 12 h; greater
than 12 to less than or equal to 24 h; and greater than 24 to less than or
equal to 36 h; P < .001). Taken together, results from this and
prior studies indicate that patients' response to tadalafil extends up to 36
hours postdose regardless of trial specifications on time from dosing until
initiation of sexual activity (eg, dosing as needed up to once daily before
expected sexual activity vs dosing followed by sexual intercourse at
prespecified times). Patients participating in this study were able to initiate sexual activity at times of their choice after dosing throughout the equilibration phase. This study design provided patients the advantage to learn how to properly use the medication and the possibility to experience successful intercourse attempts across a broad time range before being restricted to a prespecified time window during the assessment phase. On the other hand, the short duration of the equilibration phase (2 to 4 weeks), may have been a limiting factor to some patients across all treatment groups compared to the standard trial design of a 12-week treatment period during which patients have enough time to experience their response to the medication without restrictions on timing to intercourse attempts.
Patients enrolled in this study were provided with a total of 4 doses of study medication during the assessment phase and were instructed to follow each dose with a sexual intercourse attempt at their preassigned time point. The inclusion of 4 doses during the treatment (assessment) phase represents an improvement in the study design when compared to the previous trial by Porst et al (2003), which evaluated patients' response to tadalafil at 24 or 36 hours postdose using 2 doses of study medication over a 4-week treatment period for each of the 24- and 36-hour assigned times. The two additional doses used in this study, each followed by an intercourse attempt, helped reduce the variability of results within each combination of treatment group and assigned time. Patients compliance with intercourse attempts at the 24- or 36-hour assigned times postdose during the assessment phase was high across all treatment groups. Overall, about 56% of patients across all treatment groups had 4 evaluable attempts during the assessment phase. This high compliance may be attributed to the protocol instructions on timing of sexual intercourse attempts at prespecified time points after dosing.
Regardless of baseline ED severity, the mean change in the SEP3 scores from baseline to assessment phase reported by patients taking tadalafil 20 or 10 mg were greater than those of placebo-treated patients at both 24- and 36-hour assigned times (Table 3). These results show that patients with all severities of ED can benefit with the duration of effectiveness of tadalafil.
The improvement in erectile function, measured as completion of successful intercourse attempts (SEP3) observed in patients treated with tadalafil, was further corroborated by patient's increased postdose satisfaction with hardness of erection (SEP4) and overall satisfaction with the sexual experience (SEP5). The improvement seen in these secondary efficacy outcome measures was demonstrated for tadalafil-treated patients compared with placebo at each of the preassigned time periods of 24 or 36 hours (Table 4).
Tadalafil at 20- and 10-mg doses was well tolerated, with a satisfactory safety profile, when administered under the conditions described in this study. Most TEAEs were mild or moderate in severity. No clinically significant changes occurred in patients' vital signs.
This randomized, double-blind, placebo-controlled study supports the conclusion that 10- and 20-mg tadalafil significantly improves erectile function relative to placebo, based on the assessment of mean per-patient percentage of sexual attempts resulting in successful intercourse completion (SEP3), when sexual activity occurs 24 or 36 hours postdose.
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Acknowledgments |
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Footnotes |
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References |
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Saenz de Tejada I, Blanco R, Goldstein I, Azadzoi K, De Las Morenas A, Krane RJ, Cohen RA. Cholinergic neurotransmission in human corpus cavernosum. I. Responses of isolated tissue. Am J Physiol. 1988;254: H459 -H467.
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