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)
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%. The same patients also improved the
frequency and strength of their erections by 75%. There 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.
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.
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 (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, 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.
Copyright 2003. This article may not be reproduced for public
broadcast in any form, without the written permission of: International Antiaging Systems
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