International Journal of Impotence Research (2002) 14, Suppl 1, S53–S56 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir

Apomorphine SL (Uprima1): preclinical and clinical experiences learned from the first central nervous system-acting ED drug

F Giuliano1,2* and J Allard2

1Department of Urology, CHU de Biceˆtre, Assistance Publique Hoˆpitaux de Paris, France; and 2PELVIPHARM Laboratories, Domaine INRA, rue de la Guyonnerie, Bures-sur-Yvette, France

An exclusive central site of action for the proerectile effect of apomorphine, including not only the brain but also the spinal cord, is supported by extensive experimental data. Assuming that the mechanisms of action of apomorphine are similar in humans and animal models, its use for the treatment of erectile dysfunction (ED) validates the emerging idea that erectile response could be enhanced by acting directly within the central nervous system (CNS). It also emphasized the key role of the dopaminergic system in the control of erection. As exemplified with the clinical development of apomorphine, targeting the CNS does not rule out the occurrence of undesirable side effects. Because the rare event of syncope induced by apomorphine is not well understood, further research should be conducted to explore its possible mechanisms. In clinical practice, however, approved doses of apomorphine SL are well tolerated. It is noteworthy that no modification of sexual desire was observed with apomorphine. Indeed, drugs acting within the CNS may more likely interact with sexual desire than peripherally acting drugs, and care should be taken to assess this point in the future. Although our knowledge of the control of penile erection by the CNS is restricted, there are many potential sites for CNS-acting ED drugs. New centrally acting therapy for ED should concentrate on receptor targets more specific to erectile command. Clinical efficacy of new centrally-acting compounds will assess the well-founded purpose of this rationalization. International Journal of Impotence Research (2002) 14, Suppl 1, S53–S56. DOI: 10.1038= sj=ijir=3900806

Keywords: dopamine; penile erection; side effect

Introduction cell column and the dorsal grey commissure at the thoracolumbar level of the spinal cord, and the parasympathetic nuclei at the sacral level in the The semisynthetic catecholic alkaloid apomorphine, intermediolateral cell column. The spinal nuclei aD1=D2 dopaminergic (DA) receptor agonist dis- controlling penile erection are mastered by sensitive plays proerectile activity in various animal models afferences from the genitalia and descending projec- (for extensive reviews see refs 1 and 2). Moreover, tions from the brain. Apomorphine facilitates penile subcutaneous injections of low doses of apomor- erection by enhancing the release of proerectile phine (0.25 – 0.75 mg) induced penile erections in neurotransmitter(s) at the peripheral level and=or by healthy adult males and in patients with erectile decreasing the permanent antierectile tone. It can do 3,4 dysfunction (ED). Recent double-blind placebo so by acting potentially at any site along the neural controlled studies demonstrated that higher doses axis. In this brief overview are discussed outcomes of apomorphine (2 – 4 mg) delivered sublingually from the first CNS-acting ED drug. could increase the likelihood of penile erections in men with erectile dysfunction, leading to registra- tion of apomorphine SL 2 and 3 mg in Europe in May 2001.5,6 Central target of apomorphine in rats A shift of predominantly antierectile sympathetic tone in favor of proerectile parasympathetic tone is A complete set of experimental data support an 7 likely at the origin of penile erection. The sympa- exclusively central target for the proerectile effect of thetic nuclei are located in the intermediolateral peripherally delivered apomorphine in rats. First, apomorphine-induced erections are abolished by transection of the cavernous nerves8 or pelvic *Correspondence: F Giuliano, Department of Urology, CHU 9 de Biceˆtre, 78 rue du Ge´ne´ral Leclerc, 94270 Le Kremlin nerves. Apomorphine-induced erections are also Biceˆtre Cedex, France. inhibited by the central DA antagonist haloperidol, E-mail: [email protected] whereas they are unaffected by the peripheral DA Apomorphine SL: the first CNS-acting ED drug F Giuliano and J Allard S54 antagonist domperidone.10 In addition, intracaver- erection firm enough for intercourse’ in the view of nous injection of apomorphine failed to elicit penile the patient and their partner. All data have been erection.11 compiled from diary records and records were made It has long been accepted that the target for the at each attempt. A cross study analysis of the results proerectile effect of apomorphine within the CNS is of apomorphine SL trials shows that 54% of the the paraventricular nucleus of the hypothalamus attempts resulted in an erection firm enough for (PVN), as (i) injection of doses of apomorphine as intercourse at the dosing of 4 mg versus 33% with low as 5 ng in the PVN induces penile erections;12 placebo.18 In a more recent study, the dosing of 3 mg and (ii) penile erections induced by peripheral was compared with placebo. The number of delivery of apomorphine are antagonized by a attempts resulting in an erection firm enough for preceding injection of SCH23390 (D1 antagonist) or intercourse was 47% on 3 mg apomorphine and 32% sulpiride (D2 antagonist) in the PVN.11 However, on placebo.6 In all cases, successful attempts were recent data suggest that the spinal cord might also be significantly greater upon apomorphine SL (Upri- a target for the proerectile effect of apomorphine. We ma1) than placebo. It is noteworthy that these have shown that apomorphine delivered at the studies are consistent in their methodology and lumbosacral level with an intrathecal catheter primary end points, and distinct from other series of elicited erectile activity in anesthetized rats.13 studies on PDEV inhibitors.5,19 Moreover, the ability of apomorphine to induce Assuming that apomorphine acts centrally in penile erection in spinalized rats has been demon- humans as it does in the rat, the fundamental strated in both anesthetized and conscious rats.9 outcome of these clinical trials is that a drug In this era of growing interest for the neurophar- targeting the central nervous system has proved macology of erection, it is worth mentioning that efficacy for the on demand treatment of erectile apomorphine is the only proerectile drug for which dysfunction. The proerectile mechanisms of apo- an exclusive central effect has been undoubtedly morphine differs in rats (s.c. or i.v.) and humans demonstrated. Potential CNS-acting ED drug, such (s.l.) at the same dosing, although it is evident that as the alpha-MSH agonists melanotan II and PT-141 such comparison may be biased by an array of should undergo a comprehensive experimental interspecies differences not specifically related to approach similar to the one achieved with apomor- the neurophysiology of the sexual response. phine before claiming for a central mechanism of Whereas apomorphine increases the likelihood of a action.14,15 Induction of penile erections by central patient to get an erection in a relevant sexual injection of alpha-MSH in rodents does not establish context, it clearly induces erection at the same that alpha-MSH analogs such as PT-141 or melano- dosing in rats out of any sexual context (on a body tan II act through the same mechanism when given weight basis, the dosings currently used experimen- peripherally. Experimentally, it is a key point to tally in rats are similar to the ones used clinically in demonstrate that the proerectile activity observed humans, i.e. 50 – 70 mg=kg). Interestingly, close re- upon peripheral delivery of these drugs can be latives to humans such as Rhesus monkeys are also abolished by the injection of a suitable antagonist in insensitive to the prosexual activity of apomorphine the central nervous system. In this line, the ability of out of sexual context.20 Those interspecies differ- these compounds to cross the blood brain barrier ences are likely caused by differences in apomor- and the dosings required for inducing erectile phine sensitivity of the proerectile response. In activity after peripheral and central injection are support of this assertion, induction of penile essential outcomes in assessing their site of action. erections have been reported in several cases of Some hexarelin analogue peptides were also shown patients with Parkinson’s disease when self-inject- to display proerectile activity when injected in the ing 3 mg bolus apomorphine s.c. at least more than PVN of conscious rats, likely by recruiting a new four times a day.21 The weaker sensitivity of the class of receptors.16 More recently, their proerectile erectile response to apomorphine in humans points activity have been assessed when delivered periph- to the differences in the neurophysiology and erally, but it remains to be determined whether this neuropharmacology of the rat, monkey and human proerectile activity was mediated by the central central nervous system. The comparison of the nervous system.17 experimental and clinical results obtained with apomorphine underlines the cautiousness that should be exerted when extrapolating results ob- Efficacy in clinical trials: are animal models tained in animal models, and particularly in predictive for a CNS acting drug? rodents, to humans. This difficulty has been ex- emplified by yohimbine, which displays a signifi- cant proerectile efficacy in rats whereas its Phase III clinical trials with apomorphine SL proerectile effect in humans is still a matter of (Uprima1) included more than 5000 patients and debate.22 Nevertheless, apomorphine does display a over 120 000 doses. The primary efficacy endpoint significant proerectile activity in human and rats, in most studies was the presence or absence ‘of an and hence validate the use of rats as an animal

International Journal of Impotence Research Apomorphine SL: the first CNS-acting ED drug F Giuliano and J Allard S55 model in the development of CNS-drugs aiming at used in these trials.18 Nevertheless, targeting the treating erectile dysfunctions. central nervous system raises the possibility to modify sexual desire, which can be considered as positive or negative depending on individual cases. Side effects of apomorphine in humans Accordingly, a recent study established that mela- notan II, a potentially centrally acting proerectile drug, increased sexual desire upon acute dosing.26 Targeting the central nervous system obviously does not rule out the occurrence of side effects, and the clinical use of apomorphine SL is hindered by the occurrence of nausea and, rarely, syncope.23 At the Conclusion 6 mg dosing, mild to moderate nausea was reported in 34% (severe nausea, < 3%) of patients versus less The potential proerectile effect of apomorphine was than 5% with placebo. At the approved doses of 2 experimentally evidenced more than 20 y ago.10 and 3 mg, the incidence of nausea, which is Apomorphine was approved for the treatment of predominantly mild in nature, is approximately erectile dysfunction in Europe only this year. 7%. There is evidence from clinical trials of a Theoretically, a CNS acting ED drug may more tolerance to first dose nausea, where nausea occurs. likely overcome the cardio-vascular effects inherent At approved doses, syncope, the most adverse side to drugs targeting directly the erectile tissue, effect, occurs in less than 0.2% of patients. On a per because of the similarities existing between the attempt basis, this figure is very much lower. At molecular processes involved in the regulation of higher than approved doses, the incidence of all the vascular tone and local mechanisms of penile adverse events and in particular syncope is greater, erection. Ideally, CNS acting ED drugs should target while doses higher than 3 mg do not offer any neuronal pathway specifically involved in the significant incremental efficacy. For this reason, control of penile erection. Among the known the highest approved dose of apomorphine SL is candidates are oxytocinergic and a-MSH agonists 3 mg. Apomorphine-induced syncope is commonly and hexarelin analog peptides. accepted to be a vasovagal fainting induced by hypotension and might be of peripheral and=or central origin.24 Whether the concomitant delivery of a peripheral D2 antagonist, such as domperidone, References could alleviate syncope and=or nausea induced by apomorphine is an open question.25 The tolerability and safety profile of apomorphine 1 Melis MR, Argiolas A. Dopamine and sexual behavior. SL led to a narrow therapeutical window for the Neurosci Biobehav Rev 1995; 19:19– 38. 2 Giuliano F, Allard J. Dopamine and sexual function. Int J treatment of erectile dysfunction. Future CNS acting Impot Res 2001; 13: S18 – S28. ED drugs should be developed from compounds 3 Lal S et al. Effect of apomorphine, a dopamine receptor displaying first and foremost proerectile activity, agonist, on penile tumescence in normal subjects. Prog based on current basic knowledge on the central Neuropsychopharmacol Biol Psychiat 1984; 8: 695 – 699. 4 Lal S et al. Apomorphine-induced penile tumescence in pharmacology of sexual functions. This requires the impotent patients — preliminary findings. Prog Neuropsycho- recognition of proerectile targets within the CNS, pharmacol Biol Psychiat 1987; 11: 235 – 242. which will not be possible before an improvement of 5 Heaton JP. Apomorphine: an update of clinical trial results. Int our knowledge of the control of penile erection by J Impot Res 2000; 12(Suppl 4): S67 – S73. the CNS. 6 Dula E, Bukofzer S, Perdok R, George M. 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