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Viagra Beyond
Viagra®: The Latest Treatments For Erectile Dysfunction
By
Phil Micans, PharmB
Since the advent and commercial availability
of Sildenafil Citrate in 1998, (known throughout the world to one-and-all as Viagra®),
the market for treatments for erectile dysfunction has grown to become worth about
$2 billion worldwide per annum. That is now projected to grow to $4 billion per
year by the year 2004 and to an astonishing $6 billion per year by 2006! (1)
Results of recent surveys indicate that, on average, 15% of the male population
has suffered from erectile dysfunction. As a strong indicator of its age-related
increase, more than 50% of men over the age of 60 have varying degrees of erectile
dysfunction (ED). So it may not be surprising that it is estimated that ED affects
approximately 31 million men in the United States, and as a whole, there may be
as many as 300 million men around the world suffering with ED! (1)
Therefore,
to cash in on this huge and relatively new market, (at least in terms of its acceptance),
it is no surprise to discover that numerous pharmaceutical companies are rushing
to find new drugs and new methodology, to treat this sexual disease that is clearly
an age-related disorder.
That is the subject of this article, we shan't get
too bogged down in the psychology of impotence, or the social or economic impacts
of such a "disease" and its treatments. What we shall concern ourselves
with here are the pharmacokinetics, uses, interactions, effects and properties
of these revolutionary new approaches to erectile dysfunction.
Viagra®:
The Background
In order for us to ascertain the difference between the
new treatments for ED when compared to Viagra®, it is first necessary to remind
ourselves of the properties of Pfizer's stock market winner.
Viagra® is
rapidly absorbed by mouth with a bio-availability of about 40% and peak concentrations
of the chemical are in the blood within 30-120 minutes. (2) This has been one
of the advantages for Viagra®, in that it is capable of being taken as a tablet
and is relatively quick-acting. A convenient factor when perhaps one's partner
won't wait forever!
The affects of Viagra® will last, on-average, for
up to 4-hours and its metabolites are excreted in the faeces and urine. Viagra's
affect is to inhibit an enzyme known as phosphodiesterase type-5 (PDE5), which
naturally occurs in erectile tissue. PDE5 can break down cyclic GMP, the substance
that is produced during sexual arousal and causes vascular and muscular changes
that eventual lead to an erection. (2)
Therefore, men who produce too little
cyclic GMP have problems obtaining and maintaining an erection, and men who produce
too much PDE5 have problems obtaining and maintaining an erection.
Viagra®
is well known to be contraindicated with organic nitrates. These are drugs that
are often used to treat heart conditions such as hypotensive conditions, (low
blood pressure). Viagra® appears to potentiate the effects of nitrates and
therefore the two must not be taken concurrently. Furthermore, caution is advised
for any patient using Viagra® who has a heart problem, even if they are not
using nitrates for the condition. (2)
Viagra® dosages are usually 25mg
to 100mg (50mg doses being the average), taken up to one hour before sexual intercourse.
These dosages have produced side effects such as headache, flushing and dyspepsia.
There have been some reports of disturbances, dizziness, and nasal congestion.
Other rarer adverse effects reported include diarrhea, muscle pain, skin rashes,
and urinary or respiratory-tract infection. (2)
Viagra® undoubtedly represents
a very significant advance in the treatment of erectile dysfunction, but like
most drugs it is not without its cautions, contraindications and potential side
effects etc.
Alprostadil: Before Viagra®
Alprostadil is
a drug that has been available for the treatment for ED years before Viagra®
was even a twinkle in the eyes of the pharmacologists at Pfizer. Yet alprostadil
has all but disappeared as a front line treatment for ED, this is despite the
fact that some clinical trials indicate that alprostadil is as effective as Viagra®!
So why would that be?
There is one simple answer, it was because of alprostadil's
delivery method, but as we will learn, all that is about to change.
Alprostadil
is a hormone like substance that is referred to as prostaglandin E1, a known and
potent vasodilator (improver of blood flow). Alprostadil has the power to directly
effect the tissue that it comes into contact with. (3) An erection essentially
occurs when the blood vessels widen in the genital region and allow the corpus
caverosum (Figure 1) to fill with blood, and hence the penis becomes erect and
stiff. So, it is easy to see the direct role that alprostadil plays in the creation
of an erection.
Originally, alprostadil was used to treat neonates with congenital
heart defects. In order to treat this condition, alprostadil has to be directly
injected into the heart region. (4) This is the same drug that is used to treat
ED, and until very recently the delivery method was the same principle! In other
words, brand name products such as Caverject® were injected into the flaccid
tissue of the penis with fast acting results. Having spoken to some who have practiced
this method, it is apparently quite painless, but the thought of having to place
a needle into one's vital member is undoubtedly a "bridge too far" for
most men! When one considers that this is meant to take place prior to love making,
the two concepts/ thoughts just don't seem to go together!
Muse® was another
development of alprostadil that tried to reduce the psychological aspects of the
Caverject® delivery method. In essence, alprostadil was produced in intraurethral
pellets; tiny tablets that can be inserted down into the eye of the penis with
the aid of a minute insertion stick. But once again, the prospect of the delivery
method, is still too much for most men, to consider it to be a worthwhile regular
method of treatment for ED.
I think one can easily understand why Viagra®
tablets have taken the world by storm!
Alprostadil: The Recent Development
But that may now all change with the concept of an alprostadil cream. Known as
Befar®, (it may also be released later in some countries under the trade names
of Alprox® and Topiglan®), this is the first topical cream in the world
for the treatment of ED.
Currently, only commercially available in the Far
East, Befar® has shown a clinical efficacy of up to 83% in patients with varying
degrees of ED. (6) The cream itself has a onset action of 10-15 minutes and can
continue on past 4-hours, (Figure 2) and is favorably comparable to the efficacy
of the injectable alprostadil. (3, 19)
Figure 2
Due to Befar's direct
application method (i.e. unlike Viagra®, Befar's actions are limited to the
area of its application), the side effects induced by the application have to
date been limited to transient warm and burning sensations.
So instead of
using an injectable or intra-urethral pellet, Befar® cream rapidly and effectively
promotes the permeation of alprostadil into the active site of the penis.
In one randomized, double-blind, placebo-controlled, multi-center clinical trial
conducted in China (5), 157 ED patients aged 26 to 75 with various etiologies
(psychogenic, organic and a combination of both), had an mean average ED history
of 5-years. They all received treatment of Befar® or a placebo for 4-weeks.
After the 4-week period, the Befar® patients improved their ability to have
and maintain their erections by 68%, (it's noted as Primary Efficacy on Figure
3). The same patients also improved the frequency and strength of their erections
by 75%, (it's noted as Global Efficacy on Figure 3). As can be seen on the same
bar graph, this was a very significant difference over placebo.
Since then,
another trial conducted in a 303 patient phase II clinical study in the United
States has shown an impressive efficacy rate of 83% (6) Other clinical trials
support similar results. (7)
During these trials, the side effects noted have
been mild urethral pain, a feeling of urethral burning, penile fullness and redness
at the application site. Most of the adverse events were mild and transient and
all naturally resolved in a short time, without requiring any medical treatment.
Below, the chemical structure of alprostadil.
Surprisingly, Befar® may
also be suitable for women too! One study, suggested that its data supported further
investigation for topical alprostadil in the treatment of Female Sexual Arousal
Disorder (20). For whist ED is now a recognised disorder, clitoral stimulation
by vasodilatation is beginning to be seen as an important aid to sexual satisfaction
for women.
If there is a disadvantage to Befar®, it may be the fact that
it is very temperature sensitive. It is strongly recommend that Befar® (and
for that matter all alprostadil creams), remain in a fridge at a temperature of
2 to 8 degrees Celsius. The manufacturer claims that Befar® may be kept at
up to 25 degrees Celsius for up to 14-days (8), but it is clear that any temperature
in excess of that can wreak the active ingredient within hours, perhaps even minutes
if the temperature is higher still. It would appear that when temperature damage
occurs that the product takes on a clear look, rather than its normal strong white
creamy appearance. Once damaged by heat, Befar® has no active ingredient and
hence no action.
So the shipment of Befar® to-and-from the patient and
its compulsory storage conditions may be its weak-point, but from the pharmacological
and medical viewpoint Befar® is clearly a major improvement over its earlier
rivals.
Apomorphine: A New Approach
Apomorphine has been available
as a drug for many years, but the first thing that we should clear up, is that
even though it has the word "morphine" contained within its name, apomorphine
is different to morphine, and has no morphine like affects. (2, 9) For example,
where morphine is a sedative, apomorphine is a stimulant. As such, apomorphine
does not have any of the affects associated with that narcotic.
Above, the
chemical structure of apomorphine.
In the few countries where apomorphine
is currently commercially available, (those being Australia, France, Italy, Netherlands,
New Zealand and the United Kingdom), it is not a controlled substance. (2, 9,
10, 11, 12, 13)
Apomorphine is used in the control of Parkinson's disease.
Specifically, for the senile dementia, it is delivered as a subcutaneous injection
and it is used for Parkinson's because it is a dopamine agonist. In other words,
it improves the levels of the neurotransmitter that is most affected in Parkinson's
disease.
Later, it was noticed that Parkinson's patients were regularly having
penile erections after their injection. These were clearly being induced by the
apomorphine and it was soon realized that the drug may have an additional medical
role. (14) Unsurprisingly, it wasn't long before it came to the attention of a
pharmaceutical company. The first to bring an ED treatment containing apomorphine
to the market, was Abbot Laboratories of the United Kingdom. Their development
of a sublingual tablet, under the trade name of Uprima® is causing a great
deal of interest.
Apomorphine: The Development Of Uprima®
Uprima® is a potent agonist of dopamine, specifically it acts upon D1 receptor
sites, and this makes it different to the majority of ergot derived drugs for
dopamine improvement, such as, bromocriptine, which normally target D2 receptors.
(21) Accordingly, Uprima® doesn't act directly upon the penis like Viagra®
or Befar®, but instead exerts its influence in the brain for arousal, pleasure
and climax. Uprima® is known to act upon receptors in the hypothalamus, and
that this can enhance erection by increasing the signals from the brain to begin
the process. (9) Specifically, it induces selective activation in the nucleus
paraventricularis, leading to erectogenic signals. (15)
It is this brain action
that makes Uprima® a unique new approach to the treatment of ED. As Dr. Dula
stated after being involved with a trial of 1472 patients using Uprima®; "From
a urologist's perspective, it is important to understand that this is an entirely
novel agent and works totally differently to Sildenafil (Ed.- Viagra®). It
is a centrally-acting agent. What's more, apomorphine works fairly quickly, in
15-25 minutes. The main side effect is nausea, but over time and repeated dosages
it rapidly dissipates. We think that it is a safe and efficacious treatment for
erectile dysfunction." (19)
In a multi-center, double blind study (18),
520 patients (of an average median age of 54) took either 2mg, 4mg, 5mg, 6mg of
apomorphine or a placebo. The number of attempts resulting in an erection firm
enough for intercourse was recorded (Figure 4), along with the actual attempts
resulting in intercourse.
As can been seen from figures 4 and 5, the most
significant improvements over placebo are at dosages of 4mg to 6mg. However it
was clear in this same trial and others (9, 15, 16, 18), that increased dosages
also increase the likelihood of the most common side effect of nausea. (Figure
6) These side effects are reported to diminish with continued dosing. (15)
In fact, the most favorable risk/ benefit ratio is seen with a dose optimization
regimen of 3mg, with the 3mg dose providing efficacy comparable to that of 4mg,
but with fewer side effects (15).
Other side effects with Uprima® (9)
include headache, dizziness, and flushing.
Contraindications with apomorphine
include heart medications, (particularly those for hypertension) and because of
potential synergy any other dopamine agonists such as bromocriptine, hydergine,
deprenyl and L-dopa etc. Should you be taking such drugs, then always consult
with your physician before embarking upon a concurrent use of apomorphine.
As stated earlier, the average dosages of Uprima® are 2mg or 3mg taken sublingual
(dissolved under the tongue) about 15 minutes before sex. (Note that the advent
of the sublingual tablet is the only way that apomorphine should be used to treat
ED). The drug insert clearly states, that (like most ED drugs), a 3mg dose should
not be repeated again within any 8-hour period.
Conclusion:
Uprima® represents a radical new departure in the treatment of ED. Rather
than just stimulation to the penis for enhanced blood flow etc., for the first
time brain receptor sites are being targeted for enhanced sexual performance.
I am confident that we are going to see other drugs being developed along similar
lines in the coming months and years. I am also confident that similar (and even
some of the same drugs), are eventually also going to be "approved"
for sexual enhancement in females too.
References:
1.
Business Week, February 25, 2002.
2. Micromedex Martindale, International
Drug Information, June 2002
3. NexMed Research Papers, Hong Kong, June 2002.
4. Dinarevic S, Kurtagic S, Maksic H. "Use of prostaglandins in neonatal
cardiology" Med Arh 2000;54(5-6):279-82.
5. Efficacy and safety of prostaglandin
E1 cream in the treatment of erectile dysfunction. (Presented at the 9th world
meeting on impotence research, Perth Australia).
6. "Topical cream for
erectile dysfunction successfully completes phase II clinical studies." Urology,
February 2001.
7. "Alprostadil, Alprox-TD, Befar, Femprox, prostaglandin
E1 (NexMed)." Drugs R&D 1999 Dec;2(6):413-4.
8. NexMed of Hong Kong,
Befar drug leaflet, June 2002.
9. Uprima drug leaflet, June 2002, Abbot Laboratories,
United Kingdom.
10. Chemist & Druggist, June 2002 Volume 43, No. 6.
11. International Drug Directory, 2000, 17th Edition, MedPharma, Index Nominum.
12. British National Formulary, No. 42, September 2001.
13. Therapuetic
Drugs, 2nd Edition, Churchill Livingstone.
14. O'Sullivan JD, Hughes AJ,
"Apomorphine induced penile erections in Parkinson's disease." Mov.
Disord. 1998 May, 13(3):536-9.
15. Altwein JE, Keuler FU, "Oral treatment
of erectile dysfunction with apomorphine SL." Urol. Int. 2001; 67(4):257-63.
16. Mulhall JP, Bukofzer S, Edmonds AL, George M, "An open label, uncontrolled
dose optimization study of sublingual apomorphine in erectile dysfunction."
Clin. Ther. 2001 Aug;23(8):1260-71.
17. Giulano F, Allard J, Rampin O, Droupy
S, Benoit G, Alexandre L, Bernabe J, "Pro-erectile effect of systemic apomorphine:
Existence of a spinal site of action." J. Urol. 2002, Jan;167(1):402-6.
18. Padma-Nathan H, Auerbach S, Lewis R, Lewand M, Perdok R, "Efficacy and
safety of apomorphine SL vs. placebo for male erectile dysfunction." Apomorphine
study group.
19. Doctor's Guide, www.pslgroup.com
20. Islam A, Mitchel
J, Rosen R, Phillips N, Ayers C, Ferguson D, Yeager J. "Topical alprostadil
in the treatment of Female Sexual Arousal Disorder: a pilot study." : J Sex
Marital Ther 2001 Oct-Dec;27(5):531-40.
21. Rascol O. "Dopamine agonists:
what is the place of the newer compounds in the treatment of Parkinson's disease?"
J. Neural. Transm. Suppl. 1999;55:33-45.
DISCLAIMER:
ALL INFORMATION IS EDUCATIONAL AND PROVIDED UNDER IAS TERMS AND CONDITIONS. IT
DOES NOT, AND SHOULD NOT, REPLACE THE ADVICE OF YOUR PHYSICIAN.
Last
Updated: Friday, August 16, 2002
© 2002 International Antiaging Systems
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