Review Article
PHARMACEUTICAL REVIEW
M.G. WYLLIE
Libido and desire: join the club?
With the advent of sildenafil many physicians
have become, either knowingly or unwittingly,
members of both the ‘lifestyle drug’ and
‘sexual medicine’ clubs. At least in the context
of the latter, there are constraints, insofar as it
is only acceptable to ‘normalise’ sexual
activity or to rectify an imbalance; normal
erectile function can be restored effectively
using the hydraulic system re-activators, i.e.
phosphodiesterase (PDE) inhibitors. The drugs
are not approved for other situations. The
same may not be true for the former context,
however.
Although sildenafil has taken medicine to
the cusp of a new sexual revolution, it has
also generated a considerable degree of
frustration and/or unrealised expectations
within several patient groups, including non-
or poor responders to PDE inhibitors, those
with a high or indeterminate cardiovascular
risk and patients with ‘female sexual
dysfunction’. It is a salutatory lesson that,
after just over 5 years of marketing sildenafil,
it has been calculated that as few as 10% of
men with erectile dysfunction receive
treatment, and the re-prescription rate is less
than half. Furthermore, there is compelling
evidence that sildenafil (or any other PDE
inhibitor) is not particularly effective in any
more than a clinical subset of females with
sexual dysfunction.
On this basis, to meet (or perhaps cynically,
create) patient demand, the pharmaceutical
industry will have to look beyond the clinical
limitations of the hydraulic effects of PDE
inhibitors. The most obvious complementary
strategy would be based on the development
of drugs active on the CNS. However, this
immediately raises the spectre of several
social/ethical issues; namely, although many
sexual taboos have disappeared, are clinicians
really ready to enter an era of enhancing
© 2 0 0 3 B J U I N T E R N A T I O N A L | 9 2 , 3 2 3 – 3 2 4 | doi:10.1046/j.1464-410X.2003.04337.x
libido or desire? There is increasing evidence
that the pharmaceutical industry is working
on the assumption that they are.
In men, and more particularly women, there
are defined clinical subpopulations with
disorders of desire, arousal or libido. There
is no doubt that there is a medical need
for normalisation of sexuality in these
individuals. However, in terms of the logistics
of drug development, there are two issues:
can this be achieved and can it be achieved in
such a way as to have little effect on ‘normal’
sexual function, i.e. what is the potential for
recreational use? One suspects that the
unofficial position of the industry on the
latter may be different from the public façade.
Does Pfizer donate a percentage of the not
inconsiderable revenue from the ‘off label’ use
of Viagra to charity, or even to the healthcare
providers?
There are several physiological examples
illustrating the issue of normalisation vs
producing abnormal activity, a prime one
being the use of a-blockers. In hypertensive
patients with BPH, Kaplan and Kirby, amongst
others, have shown that a-blockers
effectively lower blood pressure, whereas in
normotensive individuals, apart from after the
first dose, there is little effect on blood
pressure. In this situation the drug-induced
changes are kept in check by physiological
compensatory mechanisms designed to
maintain the status quo. In terms of affective
disorders, antidepressants are effective in
treating depression but do not generally
produce mania. Closer to the andrological
field, testosterone replacement does not lead
to aggression.
Assuming similar control processes apply to
sexual function, a cursory analysis of some
of the clinically defined subpopulations of
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female sexual dysfunction indicate that it may
be possible to ‘normalise’ these without
producing aberrant types of behaviour. These
would include hypoactive sexual desire
disorder, sexual arousal disorder and orgasmic
disorder. Equally, based on an analysis of data
in men using the International Index of
Erectile Function (IIEF), a purpose for which it
was not designed, desire and libido disorders
are also highly prevalent in men. Once
again, theoretically it should be possible to
selectively ‘top up’ the deficiency in these
men.
So how can this be achieved and who is
doing what to whom? What clinicians are
immediately faced with is a plethora of
clinical anecdote and a dearth of evidence-
based medicine. Yohimbine has long been
considered to have aphrodisiac properties and
has a relatively widespread use, particularly in
Europe. Evidence of efficacy using validated
scoring systems is somewhat lacking and the
drug has a narrow therapeutic window. To
improve the clinical profile Nitromed are
developing a fixed-dose combination of a
nitric oxide-donor, L-arginine, and yohimbine.
Encouraging phase II data are available in
both men and women. The benefits of
yohimbine are a result of the blockade of
central presynaptic a2-adrenoceptors and
the side-effects are considered to be a
result of interactions with other receptors
(particularly 5-hydroxytryptamine). In an
attempt to improve on the clinical profile,
several companies developed more selective
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agents. One of these, delequamine (Syntex,
now Roche), completed phase II evaluation
where the effect on libido and desire
observed by investigators, including
Morales and Shabsigh, was considered
excellent. Unfortunately, the development
was terminated because of a small but
sustained elevation of diastolic blood
pressure, which is unacceptable for a
chronic-use drug. Like every other receptor
type, the a2 receptor has subtypes; selective
targeting of one of these has led to the
development of atipamezole (Orion). There is
encouraging (phase II) clinical data to show
that the behavioural effects in men and
women can be separated from the
haemodynamic ones.
Several dopamine agonists have been
introduced into clinical use and been
evaluated for their effects on erectile function
and/or libido and desire. There is considerable
anecdotal data (from the early 1980s) on the
benefits of quinelorane (Lilly) and the positive
effects on libido. Enthusiasm for a dopamine
agonist-based approach should be tempered
by the documented polypharmacology of
quinelorane and the lack of clinical data from
carefully controlled studies, however. Based
on the quinelorane data, apomorphine SL
(Uprima®, Abbott) would be predicted to have
an effect on libido or desire. In studies using
the IIEF this was not found to be the case,
which may reflect either the insensitivity of
the IIEF in this situation, the general efficacy
of the drug, or that the doses of apomorphine
used were too low. Apomorphine SL is
currently undergoing rigorous evaluation in
well-defined clinical subpopulations with
female sexual dysfunction, in several studies
(sponsored by TAP Pharmaceuticals) in
the USA, and in a well-documented,
subpopulation by Russell (in association with
Horizon) in Dumfries.
In the days before sildenafil, Pfizer rejected
an in-house strategy founded on a
neuropeptide-Y antagonist, based on
compelling data from animal studies.
Somewhat unusually for a neuropeptide,
there is a consistent effect on male and
female sexual behaviour throughout the
animal kingdom, from mice to primates.
The world in 1987 was not ready for a
libido-enhancing drug. Most other companies
have tried to develop subtype selective
neuropeptide-Y antagonists for a variety of
other indications, and it is likely that they are
now being evaluated in the context of sexual
medicine. However, based on current drug
development times, and assuming that a drug
results from one of the above strategies, we
will have at least 5 years to save for our
subscriptions to the libido-enhancement club!
MICHAEL G. WYLLIE, PhD
Urodoc, Herne Bay, Kent, UK
e-mail: mike@urodoc.co.uk
Next month I will examine achieving target
organ selectivity within the urogenital system
by exploiting drug delivery technologies.
© 2003 BJU INTERNATIONAL