BigKNY3 Article on Viagra does show continued need for stimulation.I enclose the whole article. This is as good as I could scan it.
The following points need to be made, for Viagra:
1) need for continued stimulation.I draw your attention to this paragraph from the original article:
"They received a single dose of
sildenafil (10, 25 or 50mg) or placebo. Each dose
was followed by visual sexual stimulation (VSS)
starting 30min post-dose and lasting for two
hours."
And again,
"The onset of penile tumescence in all the patients was within the first few minutes of commencing VSS or approximately 30 to 40min post-dosing with sildenafil, corresponding approximately with the peak plasma concentration of the compound".
Now we know from their previous studies ( Zebra posted) that duration of rigidity at these doses was 12 min max.
This is not impressive.
2)Furhtermore I am worried about side effects.
Remember that at higher doses ALL the phosphodiesterase inhibitors become NON Selective, which means they can affect the retina and the heart.
here is a quote from the recent article Newsweek Magazine article on Erectile Dysfunction:
NOVEMBER 17, 1997 NEWSWEEK 67
The third pill, Pfizer's Viagra:
marketing studies have includ-
ed men with varying degrees of
impotence,
The drug's most
common side effects include in-
digestion and headaches, and
some users report visual dis-
turbances, such as a loss of color
perception or a halo effect. But
those effects are transitory. Ex-
perts are hopeful that low-dose
co mbinations of the new pills
will boost benefits and reduce
side effects".
Well you can't have it both ways : you either jack up Viagra dose to get a better erection but then you ran the risk of side effects in the eye ( Nature article 1996 on retinal degeneration, plus possible cardiac effects ) or , you keep the dose low to minimize sideeffects i which case you get a ten minute erection.
3) A third point: Look at article No7 in th ebibliography and who do we see?
"7 Kim N, Azadzoi KM, Goldstein Irwin, De Teiada IS. A nitric
oxide-like factor mediates non-adrenergi@, non-cholinergic
relaxation of penile corpus cavernosum smooch muscle.
neurogenic JClin Invest 1991; 88: 112-118".
One of the Authors is our good friend Irwin-pad my bicycle seat- Goldstein of Barrons fame speaking poorly ov Vivus.His early work was on Nitric Oxide and I guess he sees Erectile dysfunction only from that end of the scope, gg.
***************************************************
HERE IS THE ORIGINAL VIAGRA ARTICLE
International Journal of Impotence Research (1996) 8, 47-52
C) 1996 Stockton Press.
Sildenafil: an orally active type 5 cyclic GMP-specific
phosphodiesterase inhibitor for the treatment of penile
erectile dysfunction
Mitradev Boolell, Michael f Allen, Stephen A Ballard, Sam Gepi-Attee , Gary J Muirhead,Alasdair M Naylor, Ian H Osterlohl and Clive Ginge
Pfizer Central Research, Sandwich, Kent CT13 9NJ, UK; 2 Urology Department, Southmead Hospital, Bristol, UK
ú
ú Sildenafil (ViagraTm, UK-92,480) is a novel oral agent under development for the treatment of penile erectile dysfunction. Erection is dependent on nitric oxide and its second messenger, cyclic guanosine monophosphate (cGMP). However, the relative importance of phosphodiesterase (PDE) isozymes is not clear. We have identified both CGMP- and cyclic adenosine
monophosphate-specific-- phrsphodiesterases (PDES) in human corpora cavernosa in vitro. The main PDE activity in this tissue was due to PDE5, with PDE2 and 3 also identified. Sildenafil is a selective inhibitor of PDE5 with a mean IC50 of 0.0039 gM. In human volunteers, we have shown sildenafil to have suitable pharmacokinetic and pharmacodynamic properties (rapid absorption, relatively short half-life, no significant effect on heart rate and blood pressure) for an oral agent to be taken, as required, prior to sexual activity. Moreover, in a clinical study of 12 patients with erectile dysfunction without an established organic cause, we have shown sildenafil to enhance the erectile response (duration and rigidity of erection) to visual sexual stimulation, thus highlighting the important role of PDE5 in human penile erection. Sildenafil
holds promise as a new effective oral treatment for penile erectile dysfunction.
Keywords: penile erectile dysfunction; sildenafil; oral treatment; phosphodiesterase type 5
Correspondence Dr M Boolell
Received 25 April; accepted 15 May 1996
Introduction
Penile erectile dysfunction is a common medical disorder. It has an estinaated prevalence of 2% in men aged 40 years, which increases to over 50% in men over the age of 70 years.' Penile erectile dysfunction has been defined as 'the inability to achieve and/or sustain an erection for satisfactory sexual performance .2 Generally, it is accepted that this disorder adversely affects quality of life' Patients often report increasing anxiety, loss of self-esteem, lack of self-confidence, tension and difficulty in the relationship with their partner.2
Penile erection is a haemodynamic event which is dependent upon relaxation of the smooth muscle cells of the corpus cavernosum and of its associated arterioles, with consequential increase in arterial flow into the trabecular spaces of the corpora cavernosa. 3,4 The increased blood flow causes the lacunar spaces or sinusoids to become distended which results in compression of the small venules between the sinusoids and the tunica albuginea. The relative indistensibility of the tunica albuginea results in a veno-occlusive effect such that the penile pressure increases to approach mean arterial pressure and penile rigidity develops.
There is now ample evidence from both animal experiments and in vitro studies with human tissue to suggest that relaxation of the smooth muscle of the corpora cavernosa is mediated by nitric oxide via cyclic guanosine monophosphate (cGNT). 5-8 During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells. Nitric oxide then stimulates the cytosolic enzyme guanylate cyclase to produce CGNT which results in a decrease in intracellular calcium and allows relaxation of smooth muscle cells. Cyclic nucleotide phosphodiesterase (PDE) isozymes, which are distributed in various tissues, specifically hydrolyse cyclic nucleotides, such as cGNM.9 Therefore, a pharmacological agent which inhibits the cGNT-specific phosphodiesterase isozyme, should enhance the action of nitric oxide/cGNT on penile erectile activity and have the potential to enhance penile erections during sexual stimulation.
To date, pharmacological therapy for penile erectile dysfunction has been largely based on the use of intracavernosal injections of vasoactive agents. Though efficacious, this form of therapy is associated with a high dropout rate for a variety of reasons.10 Recent insights into the mechanism of penile erection have, however, led to the devel-
Pharmacokinetic studies
The following studies have been conducted to
investigate the single oral dose pharmacokinetics
of sildenafil.
(i) A single-blind, escalating single oral dose
study, in which solution doses ranging from
1.25 to 90mg were administered to two
groups (n = 9 and n = 10) of healthy male
volunteers, with random insertion of placebo.
Each subject received three active doses and
placebo.
(ii) An extension of the first study in which a
group of 10 healthy male volunteers received
single oral solution doses of sildenafil (100,
150 and 200mg) with random insertion of
placebo.
(iii) An open, randomised, two-way cross-over study to
investigate the pharmacokinetics of sildenafil
after oral administration (50mg
capsule) and intravenous administration
(50 mg) to a group of 12 healthy male volun-
teers.
In all studies blood samples were taken pre-dose
and at intervals up to 72 h post-dose for determi-
nation of the plasma concentrations of sildena:ral.
Plasma and urine samples were assayed using a
sensitive and specific HPLC assay following solid
phase extraction.
Clinical study
The efficacy of sildenafil on penile erectile activity
was evaluated in 12 patients who had a history of
penile erectile dysfunction of at least six months
duration. On clinical evaluation there was no
obvious organic cause for penile erectile dys-
function. Patients were excluded from the study if
there was evidence of neurovascular disease on
Clinical evaluation, diabetes, drug or alcohol
abuse, or other established causes for their penile
erectile dysfunction.
The study was a double-blind, placebo-
controlled, randomised, four-way crossover design. .
A period of at least three days was allowed
between consecutive treatment periods to ensure
that there was adequate clearance of sildenafil
from the circulation. On each dosing period,
patients were admitted to a hospital bed with
complete privacy. They received a single dose of
sildenafil (10, 25 or 50mg) or placebo. Each dose
was followed by visual sexual stimulation (VSS)
starting 30min post-dose and lasting for two
hours. VSS was provided by viewing of sexually
explicit material chosen from a selection of videos
and magazines. Drug efficacy on penile erectile
activity was evaluated by measurement of penile
rigidity at the base and tip of the penis by penile
plethysmography (RigiScan, Dacomed Corpora-
ion). The study was approved by the local ethics
committee.
Mean duration of rigidity of greater than 60% at the base and tip of the penis was analysed by analysis of variance (ANOVA).
Results
Phosphodiesterase activities in human corpus cavemosum
Two major peaks demonstrating CGMP hydrolytic activity and one peak demonstrating CAMP hydrolytic activity were resolved by anion exchange chromatographic analysis of soluble fractions from human corpus cavernosilm (Figure 1). Peak 1, which had the greatest PDE activity, was found in soluble fractions prepared from three separate samples of human corpus cavernosum. The PDE activity in the peak was specific for CGNT as substrate and unaffected by calcium calnaodulin.
( shows graph, which could not be duplicated )
Figure 1 Separation of PDE isoenzymes from human corpus cavernosum by fast protein liquid chromatography on a Mono-Q column. Panel (a) shows hydrolysis of CGNT (0.5 JIM) in the presence and absence of loorun sildenafil. Panel (b) shows hydrolysis of CAMP (0.5pM) in the presence and absence of loo nm sildenafil. Each point represents the mean of three replicate assays.
There were no clinically signifiicant eefects on pulse rate, blood pressure and laboratory safety tests ( haematology and biochemistry proiles ) following asministration of single oral doses of up to 200 mg to healthy volunteers.The main adverse effects reported following doses of 90 mg and above were headache and facial flushing. These adverse events were of mild to moderate severity and resolved spontaneously after a few hours. There were no treatment-related discontinuations.
Clinical efficacy
For the 12 patients entering the clinical study, the mean age was 48 years (range 36 to 63) and the mean duration of penile erectile dysfunction 3.4years (range 1.5 to 10).
Two patients were excluded from the ANOVA analysis of mean duration of rigidity of greater than 60% at the base and tip of the penis. One
patient had an erection of greater than 60% rigid-
ity which started prior to VSS in the period when
he received 25 mg of sildenafil. The second patient
was excluded because penile plethysmography
was not recorded due to technical difficulties.
The duration of rigidity of greater than 60% at
the base and tip of the penis during VSS was sig-
nfficantly higher in each treatment group com-
pared with placebo (Figure 4). The geometric mean
duration (in min) of rigidity of greater than 60%
the base of the penis was 3.2 (95% confidence interval 1.1 to 7.9) on placebo, 25.9 (11.7 to 56.8, P = 0.001) on 10 mg, 24.1 (10.3 to 55.8, P = 0.003) on 25 mg and 31.8 (14.4 to 69.6, P = 0.001) on 50mg of sildenafil. The corresponding values at the tip of the penis were 3.0 (95% confidence interval 1.3 to 6.4) on placebo, 19.1 (9.8 to 36.8, P = 0.001) on 10 mg, 26.3 (13.0 to 52.7, P = 0.001) on 25 mg and 26.5 (13.7 to 50.8, P = 0.001) on 50mg of sildenafil. The onset of penile tumescence in all the patients was within the first few minutes of commencing VSS or approximately 30 to 40min post-dosing with sildenafil, corresponding approximately with the peak plasma concentration of the compound.
Four patients (two at 25 mg and two at 50mg) reported mild headache. There was no discontinuation from the study due to these adverse events, which were mild and transient. Importantly, there were no significant changes in pulse rate, blood pressure or laboratory safety data in these patients.
Discussion and conclusion
During recent years it has become increasingly
clear that the nitric oxide-cGNT system plays a
key role in the local mechanism of penile erec-
tion. 5-8 We have demonstrated the presence of
PDE2, 3 and 5 in human corpora cavernosa, and
shown that sildenafil is a potent selective inhibi-
tor of hilmqn PDE5. Furthermore, the clinical data
obtained with sildenafil highlight the iiiaportant
role of PDE5 in human penile erection.
Our finding that cGNT-specific PDE5 was the
major CGNT phosphodiesterase activity isolated
from human corpus cavernosum and that CGNT-inhibited PDE3 was also present is in agreement with the report of Stieff et al.18 In general, tissues such as corpus cavernosal smooth muscle, in
which CGNV and cAlvT appear to have similar
physiological effects, express PDE3 in addition to
the cGNT-specifac phosophodiesterase.19, 20 This
allows CGMP and CAMP to work synergistically in
the tissue. 2 0 We have previously demonstrated
that sildenafil potentiates relaxation of
phenylephriiae-contracted human corpus caver-
nosilm elicited by electrical field stimulation,21
and endothelium-dependent relaxation of rabbit
cavernosal tissue induced by the muscarinic
agonist, methacholine 22.In both cases the effects
of sildenafil were dependent on activation of the
nitric oxide-cGMP mediated relaxation pathway.
This may explain why Stieff et al. 18, who exam
ined relaxation of cavernosal tissue without
stimulation by nitric oxide, found that the selec-
tive PDE5 inhibitor, zaprinast, was a weaker and
less effective elaxant of human cavernosal tisues
than PDE3 selectiveagents.
By selectively inhibiting the type 5 CGMP specific phosphodiesterase, sildenafil improves
penile erectile activity in patients with erectile
dysfunction during sexual stimulation. Experimental evidence indicates that this is a local action of sildenafil on the corpus cavernosal smooth muscle cells where it enhances nitric oxide mediated relaxation. 21,22 We believe that under conditions of nitric oxide drive, type 5 PDE is the
most important regulator of CGMP levels in the corpus cavernosal smooth muscle cell. The mechanism of action of sildenafil suggests that it will induce or enhance erections during sexual stimulation, but will not provide erections in the absence of any physiological or sexual stimulus.
Sildlenafil demonstrates ideal pharmacokinetics for an oral agent to be taken, as required, prior to sexual activity for the treatment of penile erectile dysfunction. It is rapidly absorbed when adminis-tered orally, and has an onset of action of less than one hour. Furthermore, the drug has a relatively short plasma half life of approximately 4 h and is not expected to accumulate on repeated single daily administration. In the dose range studied, sildenafil is generally well tolerated and has no significant effects on pulse rate and blood pressure.
Sildenafil represents a new class of orally active
and peripherally acting drug for the treatment of
penile erectile dysfunction. The RigiScan study
demonstrates that sildenafil enhances the erectile
response to erotic stiinuli under standardised con-
ditions. The results are reported in terms of mean
duration of rigidity of greater than 60%. Although
There is considerable debate as to the threshold
degree of rigidity which correlates with sufficient hardness for penetrative intercourse, previous
studies indicate that the vast majority of patients
who achieve 60% rigidity will have an erection
that is sufficient for sexual intercourse. 23,24 its
efficacy in enhancing erections during stimulation
in the natural and private setting and its safety on
long-term adminstration are currently being inves-
tigated in large-scale clinical trials.
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