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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 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 α-blockers. In hypertensive patients with BPH, Kaplan and Kirby, amongst others, have shown that α-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 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 α2-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 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 α2 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!

Next month I will examine achieving target organ selectivity within the urogenital system by exploiting drug delivery technologies.