- Email: [email protected]
Apomorphine SL: Evolution of a Centrally Acting Treatment for Erectile Dysfunction
European Urology Supplements
European Urology Supplements 1 (2002) 1±3
Apomorphine SL: Evolution of a Centrally Acting Treatment for Erectile Dysfunction Francois Giuliano* Department of Urology, CHU de Bicetre, AP-HP, 78 rue du General Leclerc, 94270 Le Kremlin-Bicetre Cedex, France
Abstract Erectile dysfunction has been described in the medical literature since ancient times. Developments in Western medicine included the development of vascular procedures, vacuum devices, penile implants, intracavernosal and intraurethral therapies, and most recently, oral drugs: sildena®l and sublingual apomorphine. Apomorphine has a central mechanism of action, but also reinforces peripheral neuronal pathways. The hypothalamus plays a critical role in the central command of penile erection. Erectile function also depends on neurotransmitters, most notably dopamine, serotonin, norepinephrine, oxytocin, and nitric oxide. Apomorphine has predominant D2-like dopamine receptor agonist effects and acts primarily on the paraventricular nucleus of the hypothalamus, promoting the natural erectile phenomenon and assisting in the restoration of normal autonomic balance in the control of penile function. The drug has a long history of safety in humans and is absorbed rapidly by the oral mucosa. Onset of action is rapidÐusually within 20 minutes of administration. The most distinct adverse effects of the drug are nausea, dizziness and yawning. Potential drug interactions are unlikely. The drug has no addictive or analgesic properties. Clinical trials indicate that sublingual apomorphine is effective in helping men with erectile dysfunction achieve satisfactory penile erections. # 2002 Published by Elsevier Science B.V. Keywords: Apomorphine; Sildena®l; Erectile dysfunction
Erectile dysfunction has been described in the medical literature since ancient times. Historical documents from China's Jin Dynasty (third and fourth centuries A.D.) indicate that the disorder had long been recognized as a disease in ancient Chinese medicine [1]; it referred to the inability to attain erection despite the desire to do so. The most recent NIH de®nition of erectile dysfunction is ``the consistent inability to achieve or maintain an erection ®rm enough for satisfactory sexual performance''. As early as 1860, researchers in Western medicine attempted to study the neural and vascular phenomena responsible for male sexual tumescence, leading to the development of various treatment strategies for impotence later in the 19th century [2]. Vascular procedures were developed early in the 20th century, and a vacuum device was introduced in 1913 [3]. The ®rst penile implants, * Tel. 33-1-4521-3698; Fax: 33-1-4521-2170. E-mail address: [email protected] (F. Giuliano).
consisting of cartilage and bone, were described in 1936 but were unsuccessful because of resorption after several months [3]. Acrylic prostheses were introduced in 1952 [4]. Intracavernosal and intraurethral therapies were later innovations that are still in use today [3]. However, not until the late 1990s was the ®eld of erectile dysfunction therapy truly revolutionized with the introduction of an effective oral drug. Oral drugs used to treat erectile dysfunction have either a peripheral or a central mode of action [5]. Sildena®l, the ®rst widely used oral agent, acts peripherally. A second oral drug, apomorphine SLÐthe topic of this supplementÐ was introduced shortly afterward. Because the pathways involved in the sexual response are complex and incompletely understood, the promise of centrally active drugs such as apomorphine are only now being explored fully. Apomorphine SL has a central mechanism of action, although it also reinforces peripheral neuronal pathways. The advantage of centrally acting agents is that
1569-9056/02/$ ± see front matter # 2002 Published by Elsevier Science B.V. PII: S 1 5 6 9 - 9 0 5 6 ( 0 2 ) 0 0 0 0 7 - 6
2
F. Giuliano / European Urology Supplements 1 (2002) 1±3
they stimulate speci®c groups of neurons in the central nervous system to trigger a neuronal cascade; this, in turn, takes advantage of the natural ampli®cation of sexual signaling that occurs between the central nervous system and the periphery [6]. While the peripheral vasculature is important in producing erection, the phenomenon of penile erection is under the control of the central nervous system. Penile erection relies upon tumescence of the cavernous bodies, which, in turn, depends upon integration of complex neural and humoral mechanisms in the neuroaxis. It is unique among visceral functions in its requirement for central neural input before it can occur, making a central mechanism of action feasible and desirable from a therapeutic standpoint. Signals received by the brain and integrated into the sexual response may be fantasy- or memory-based, visual, tactile, and/or olfactory. The efferent response is initiated via the autonomic nervous system at the hypothalamic level. The hypothalamus plays a critical role in the central command of penile erection by mainly functioning through two nuclei: the medial preoptic area and the paraventricular nucleus [7] (Fig. 1). The medial preoptic area is in intimate contact with different regions of the brain and integrates signals from both central and peripheral sources. The paraventricular nucleus has direct neural connections with the spinal cord. Parasympathetic impulses from segments S2 to S4 of the spinal cord provide the major excitatory stimuli to the penis and initiate the vasodilation as well as the relaxation of smooth muscle of the erectile tissue; both are responsible for erection. These efferent axons travel
Fig. 1. Hierarchical control of sexual re¯exes originating in visual, tactile, olfactory and/or imaginative stimuli and leading to male penile erection. Adapted from [9] and [15].
through the pelvic nerve, then the cavernous nerves after synapsing in the pelvic plexus to the penis. Prefatory to the elucidation of the neurophysiology of erection in humans, this mechanism was demonstrated in rats [8]. To function effectively, the male sexual organ requires the participation of several neurotransmitters; those in the central nervous system include dopamine, serotonin, norepinephrine, oxytocin, and nitric oxide [9]. The participation of dopamine was ®rst suggested by the occasional ®nding of increased sexual activity in Parkinson's patients treated with certain dopamine agonists in the 1960s. Apomorphine, in particular, was found to suppress the refractory motor oscillations of the disease; at the same time, in a few male patients, the drug stimulated erection [10]. Subsequent studies demonstrated that apomorphine, a semisynthetic dopamine receptor agonist, could induce erections in men with erectile dysfunction. Until recent large-scale studies of apomorphine SL, the link between sexual function and dopamine in human males was unclear, although animal studies had clearly demonstrated the link [8]. Apomorphine has been demonstrated to have predominant D2-like dopamine receptor agonist effects [11]. The drug acts primarily in the paraventricular nucleus of the hypothalamus [12], promoting the natural erectile phenomenon and assisting in the restoration of normal autonomic balance in the control of penile function. In addition, uncharacterized actions of the drug in the central nervous system may contribute to the drug's overall ef®cacy. The development of apomorphine SL to enhance erectile function opened a new era in the use of central nervous system drugs for the management of sexual dysfunction [13]. The drug was known to have an appropriate mechanism of action and, since its initial discovery in the 1890s, a history of safety in humans. Subsequent clinical trials of apomorphine SL clearly demonstrated its ef®cacy in male erectile dysfunction. In the sublingual formulation, the agent is absorbed rapidly by the mucosa of the oral cavity. The rapid onset of action is demonstrated by a swift clinical response, such that the majority of responding patients do so within 20 minutes of administration. If swallowed, the medication loses 98±99% of its bioactivity. Apomorphine SL has a favorable safety pro®le in all the populations studied to date, including those with common comorbidities associated with the cardiovascular system. The metabolic routes of elimination for this agent render potential drug interactions unlikely, a relevant consideration given the average age and pharmacotherapy pro®le of these patients. The most distinct adverse effects with apomorphine are nausea, dizziness and yawning. Although relatively uncommon (<0.1%),
F. Giuliano / European Urology Supplements 1 (2002) 1±3
a vasovagal response can occur, which is typically preceded by a prodrome that provides a forewarning, allowing a patient and his partner to adapt appropriately. While the name ``apomorphine'' includes the term ``morphine'', the drug has no addictive or analgesic properties. Apomorphine is synthesized by a chemical rearrangement of the morphine molecule in such a way that the molecule has little similarity to morphine and none of its narcotic characteristics [11]. The availability of oral therapy for erectile dysfunction has changed the lives of millions of men and their sexual partners. Now, an oral drug with a central mechanism of action is a therapeutic option for these men. Over 5000 men with all degrees of disease severity have participated in clinical trials of apomorphine SL [14]. These men have suffered from erectile
3
dysfunction associated with a broad spectrum of comorbidities: cardiovascular disease, hypertension, hyperlipidemia, and diabetes mellitus, among others. Many of the men have been receiving concomitant antihypertensive medication, or anti-angina drugs such as nitrates. Over one third of the men in the apomorphine SL study population have had severe erectile dysfunction, resulting in therapeutic ®ndings that may be re¯ective of more severe dysfunction than that seen in the general population. As the reports in this supplement make clear, apomorphine SL is capable of redressing neuronal network imbalances and enhancing the efferent transmission of neuronal signals, initiated by sexual stimulation, in such a way as to produce a satisfactory penile erection in men with otherwise inadequate erectile function.
References [1] Qin G. A study on evolution of the term impotence and its classi®cation and diagnosis. Zhonghua Yi Shi Za Zhi 2000;30:28±31. [2] Das S. Early history of venogenic impotence. Int J Impot Res 1994;6: 183±9. [3] Jonas U. The history of erectile dysfunction. Int J Impot Res 2001; 13(Suppl 3):S3±7. [4] Gee WF. A history of surgical treatment of impotence. Urology 1975; 5:401±5. [5] Krane R, Brock G, Eardley I, Fourcroy J, Giuliano F, Hutter C, Teloken C, Vickers M. Oral nonendocrine treatment in erectile dysfunction. In: Jardin A, Wagner G, Khoury S, Giuliano F, PadmaNathan H, Rosen R, editors. Proceedings of the First International Consultation on Erectile Dysfunction co-sponsored by WHO and ICED. Oxford: Health Publication Ltd., 2000, pp. 241±303. [6] Heaton JPW. Neural and pharmacological determinants of erection. Int J Impot Res 1996;10(Suppl 2):S35±9. [7] Rampin O. Mode of action of a new oral treatment for erectile dysfunction: Apomorphine SL. BJ Urol Int 2001;88(Suppl 3): 22±4.
[8] Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: Site of action in brain. Brain Res 1987;415: 98±104. [9] Giuliano F, Allard J. Dopamine and sexual function. Int J Impot Res 2001;13(Suppl 3):S18±28. [10] Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modi®cation of parkinsonism. N Engl J Med 1967;276:374±9. [11] Argiolas A, Hedlund H. The pharmacology and clinical pharmacokinetics of apomorphine SL. BJ Urol Int 2001;88(Suppl 3):18±21. [12] Melis MR, Argiolas A. Dopamine and sexual behavior. Neurosci Biobehav Rev 1995;19:19±38. [13] Heaton JPW. Characterising the bene®t of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction. Int J Impot Res 2001;13(Suppl 3):S35±9. [14] Wagner G. Apomorphine SL (Uprima): A new treatment for the management of erectile dysfunction. Int J Impot Res 2001;13(Suppl 3): S1±2. [15] Andersson K-E. Neurophysiology/pharmacology of erection. Int J Impot Res 2001;13(Suppl 3):S8±S17.
European Urology Supplements 1 (2002) 1±3
Apomorphine SL: Evolution of a Centrally Acting Treatment for Erectile Dysfunction Francois Giuliano* Department of Urology, CHU de Bicetre, AP-HP, 78 rue du General Leclerc, 94270 Le Kremlin-Bicetre Cedex, France
Abstract Erectile dysfunction has been described in the medical literature since ancient times. Developments in Western medicine included the development of vascular procedures, vacuum devices, penile implants, intracavernosal and intraurethral therapies, and most recently, oral drugs: sildena®l and sublingual apomorphine. Apomorphine has a central mechanism of action, but also reinforces peripheral neuronal pathways. The hypothalamus plays a critical role in the central command of penile erection. Erectile function also depends on neurotransmitters, most notably dopamine, serotonin, norepinephrine, oxytocin, and nitric oxide. Apomorphine has predominant D2-like dopamine receptor agonist effects and acts primarily on the paraventricular nucleus of the hypothalamus, promoting the natural erectile phenomenon and assisting in the restoration of normal autonomic balance in the control of penile function. The drug has a long history of safety in humans and is absorbed rapidly by the oral mucosa. Onset of action is rapidÐusually within 20 minutes of administration. The most distinct adverse effects of the drug are nausea, dizziness and yawning. Potential drug interactions are unlikely. The drug has no addictive or analgesic properties. Clinical trials indicate that sublingual apomorphine is effective in helping men with erectile dysfunction achieve satisfactory penile erections. # 2002 Published by Elsevier Science B.V. Keywords: Apomorphine; Sildena®l; Erectile dysfunction
Erectile dysfunction has been described in the medical literature since ancient times. Historical documents from China's Jin Dynasty (third and fourth centuries A.D.) indicate that the disorder had long been recognized as a disease in ancient Chinese medicine [1]; it referred to the inability to attain erection despite the desire to do so. The most recent NIH de®nition of erectile dysfunction is ``the consistent inability to achieve or maintain an erection ®rm enough for satisfactory sexual performance''. As early as 1860, researchers in Western medicine attempted to study the neural and vascular phenomena responsible for male sexual tumescence, leading to the development of various treatment strategies for impotence later in the 19th century [2]. Vascular procedures were developed early in the 20th century, and a vacuum device was introduced in 1913 [3]. The ®rst penile implants, * Tel. 33-1-4521-3698; Fax: 33-1-4521-2170. E-mail address: [email protected] (F. Giuliano).
consisting of cartilage and bone, were described in 1936 but were unsuccessful because of resorption after several months [3]. Acrylic prostheses were introduced in 1952 [4]. Intracavernosal and intraurethral therapies were later innovations that are still in use today [3]. However, not until the late 1990s was the ®eld of erectile dysfunction therapy truly revolutionized with the introduction of an effective oral drug. Oral drugs used to treat erectile dysfunction have either a peripheral or a central mode of action [5]. Sildena®l, the ®rst widely used oral agent, acts peripherally. A second oral drug, apomorphine SLÐthe topic of this supplementÐ was introduced shortly afterward. Because the pathways involved in the sexual response are complex and incompletely understood, the promise of centrally active drugs such as apomorphine are only now being explored fully. Apomorphine SL has a central mechanism of action, although it also reinforces peripheral neuronal pathways. The advantage of centrally acting agents is that
1569-9056/02/$ ± see front matter # 2002 Published by Elsevier Science B.V. PII: S 1 5 6 9 - 9 0 5 6 ( 0 2 ) 0 0 0 0 7 - 6
2
F. Giuliano / European Urology Supplements 1 (2002) 1±3
they stimulate speci®c groups of neurons in the central nervous system to trigger a neuronal cascade; this, in turn, takes advantage of the natural ampli®cation of sexual signaling that occurs between the central nervous system and the periphery [6]. While the peripheral vasculature is important in producing erection, the phenomenon of penile erection is under the control of the central nervous system. Penile erection relies upon tumescence of the cavernous bodies, which, in turn, depends upon integration of complex neural and humoral mechanisms in the neuroaxis. It is unique among visceral functions in its requirement for central neural input before it can occur, making a central mechanism of action feasible and desirable from a therapeutic standpoint. Signals received by the brain and integrated into the sexual response may be fantasy- or memory-based, visual, tactile, and/or olfactory. The efferent response is initiated via the autonomic nervous system at the hypothalamic level. The hypothalamus plays a critical role in the central command of penile erection by mainly functioning through two nuclei: the medial preoptic area and the paraventricular nucleus [7] (Fig. 1). The medial preoptic area is in intimate contact with different regions of the brain and integrates signals from both central and peripheral sources. The paraventricular nucleus has direct neural connections with the spinal cord. Parasympathetic impulses from segments S2 to S4 of the spinal cord provide the major excitatory stimuli to the penis and initiate the vasodilation as well as the relaxation of smooth muscle of the erectile tissue; both are responsible for erection. These efferent axons travel
Fig. 1. Hierarchical control of sexual re¯exes originating in visual, tactile, olfactory and/or imaginative stimuli and leading to male penile erection. Adapted from [9] and [15].
through the pelvic nerve, then the cavernous nerves after synapsing in the pelvic plexus to the penis. Prefatory to the elucidation of the neurophysiology of erection in humans, this mechanism was demonstrated in rats [8]. To function effectively, the male sexual organ requires the participation of several neurotransmitters; those in the central nervous system include dopamine, serotonin, norepinephrine, oxytocin, and nitric oxide [9]. The participation of dopamine was ®rst suggested by the occasional ®nding of increased sexual activity in Parkinson's patients treated with certain dopamine agonists in the 1960s. Apomorphine, in particular, was found to suppress the refractory motor oscillations of the disease; at the same time, in a few male patients, the drug stimulated erection [10]. Subsequent studies demonstrated that apomorphine, a semisynthetic dopamine receptor agonist, could induce erections in men with erectile dysfunction. Until recent large-scale studies of apomorphine SL, the link between sexual function and dopamine in human males was unclear, although animal studies had clearly demonstrated the link [8]. Apomorphine has been demonstrated to have predominant D2-like dopamine receptor agonist effects [11]. The drug acts primarily in the paraventricular nucleus of the hypothalamus [12], promoting the natural erectile phenomenon and assisting in the restoration of normal autonomic balance in the control of penile function. In addition, uncharacterized actions of the drug in the central nervous system may contribute to the drug's overall ef®cacy. The development of apomorphine SL to enhance erectile function opened a new era in the use of central nervous system drugs for the management of sexual dysfunction [13]. The drug was known to have an appropriate mechanism of action and, since its initial discovery in the 1890s, a history of safety in humans. Subsequent clinical trials of apomorphine SL clearly demonstrated its ef®cacy in male erectile dysfunction. In the sublingual formulation, the agent is absorbed rapidly by the mucosa of the oral cavity. The rapid onset of action is demonstrated by a swift clinical response, such that the majority of responding patients do so within 20 minutes of administration. If swallowed, the medication loses 98±99% of its bioactivity. Apomorphine SL has a favorable safety pro®le in all the populations studied to date, including those with common comorbidities associated with the cardiovascular system. The metabolic routes of elimination for this agent render potential drug interactions unlikely, a relevant consideration given the average age and pharmacotherapy pro®le of these patients. The most distinct adverse effects with apomorphine are nausea, dizziness and yawning. Although relatively uncommon (<0.1%),
F. Giuliano / European Urology Supplements 1 (2002) 1±3
a vasovagal response can occur, which is typically preceded by a prodrome that provides a forewarning, allowing a patient and his partner to adapt appropriately. While the name ``apomorphine'' includes the term ``morphine'', the drug has no addictive or analgesic properties. Apomorphine is synthesized by a chemical rearrangement of the morphine molecule in such a way that the molecule has little similarity to morphine and none of its narcotic characteristics [11]. The availability of oral therapy for erectile dysfunction has changed the lives of millions of men and their sexual partners. Now, an oral drug with a central mechanism of action is a therapeutic option for these men. Over 5000 men with all degrees of disease severity have participated in clinical trials of apomorphine SL [14]. These men have suffered from erectile
3
dysfunction associated with a broad spectrum of comorbidities: cardiovascular disease, hypertension, hyperlipidemia, and diabetes mellitus, among others. Many of the men have been receiving concomitant antihypertensive medication, or anti-angina drugs such as nitrates. Over one third of the men in the apomorphine SL study population have had severe erectile dysfunction, resulting in therapeutic ®ndings that may be re¯ective of more severe dysfunction than that seen in the general population. As the reports in this supplement make clear, apomorphine SL is capable of redressing neuronal network imbalances and enhancing the efferent transmission of neuronal signals, initiated by sexual stimulation, in such a way as to produce a satisfactory penile erection in men with otherwise inadequate erectile function.
References [1] Qin G. A study on evolution of the term impotence and its classi®cation and diagnosis. Zhonghua Yi Shi Za Zhi 2000;30:28±31. [2] Das S. Early history of venogenic impotence. Int J Impot Res 1994;6: 183±9. [3] Jonas U. The history of erectile dysfunction. Int J Impot Res 2001; 13(Suppl 3):S3±7. [4] Gee WF. A history of surgical treatment of impotence. Urology 1975; 5:401±5. [5] Krane R, Brock G, Eardley I, Fourcroy J, Giuliano F, Hutter C, Teloken C, Vickers M. Oral nonendocrine treatment in erectile dysfunction. In: Jardin A, Wagner G, Khoury S, Giuliano F, PadmaNathan H, Rosen R, editors. Proceedings of the First International Consultation on Erectile Dysfunction co-sponsored by WHO and ICED. Oxford: Health Publication Ltd., 2000, pp. 241±303. [6] Heaton JPW. Neural and pharmacological determinants of erection. Int J Impot Res 1996;10(Suppl 2):S35±9. [7] Rampin O. Mode of action of a new oral treatment for erectile dysfunction: Apomorphine SL. BJ Urol Int 2001;88(Suppl 3): 22±4.
[8] Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: Site of action in brain. Brain Res 1987;415: 98±104. [9] Giuliano F, Allard J. Dopamine and sexual function. Int J Impot Res 2001;13(Suppl 3):S18±28. [10] Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modi®cation of parkinsonism. N Engl J Med 1967;276:374±9. [11] Argiolas A, Hedlund H. The pharmacology and clinical pharmacokinetics of apomorphine SL. BJ Urol Int 2001;88(Suppl 3):18±21. [12] Melis MR, Argiolas A. Dopamine and sexual behavior. Neurosci Biobehav Rev 1995;19:19±38. [13] Heaton JPW. Characterising the bene®t of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction. Int J Impot Res 2001;13(Suppl 3):S35±9. [14] Wagner G. Apomorphine SL (Uprima): A new treatment for the management of erectile dysfunction. Int J Impot Res 2001;13(Suppl 3): S1±2. [15] Andersson K-E. Neurophysiology/pharmacology of erection. Int J Impot Res 2001;13(Suppl 3):S8±S17.