Effects of oral phentolamine, taken before sleep, on nocturnal

International Journal of Impotence Research (2001) 13, 303–308
ß 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 8.13 and mean duration of ED
31.8 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 ¼ 0.02), as well as the rigidity activity units (RAU) value per hour sleep, both at the base
(P ¼ 0.023) and the tip of the penis (P ¼ 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, 303–308.
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 — mainly due to the availability of
oral agents in the market — 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 patient’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 s.e. The Student’s
t-test was used for comparative statistical analysis as
appropriate.
Results
Five patients, 29 to 49-y-old (mean s.d: 34.8 8.13 y), formed the study sample. Duration of ED
was 31.8 23.56 months (range 8 – 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 – 21.38 h) and for the phentolamine sessions 92.38 h (range 16.33 – 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 0.15) versus the
phentolamine (0.6 0.12) sessions (P ¼ 0.29). Phentolamine administration was associated with increased mean number of erectile events per sleep
hour (0.13 þ 0.05 vs 0.24 þ 0.08, P ¼ 0.02). Increased
duration of these erectile events was also noticed
(2.6 1.04 for placebo vs 5.53 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 0.15
(55)
0.6 0.12
(54)
0.13 0.05
(12)
0.24 0.08*
(22)
2.6 1.04
(248)
5.53 2.57
(489)
*P < 0.05. PHE ¼ 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 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 1.21
(468)
4.16 1.33
(410)
5.16 0.73
(465)
5.77 1.62
(560)
8.25 1.39*
(740)
5.24 1.6
(515)
7.29 1.79*
(644)
*P < 0.05. PHE ¼ phentolamine.
International Journal of Impotence Research
Effects of phentolamine on nocturnal erection
DG Hatzichristou et al
306
mine, P ¼ 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 1.47 for
placebo vs 5.28 1.21 for phentolamine, P ¼ 0.33)
and the tip (4.16 1.33 vs 5.16 0.73, P ¼ 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 1.62 for placebo and 8.25 1.39 for phentolamine (P ¼ 0.023). At the tip of the penis, mean
RAU=h was 5.24 1.6 for the placebo, compared
with 7.29 1.79 after phentolamine administration
(P ¼ 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 – 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 ‘proof of the concept’ 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.
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