Manon Auffret
email: auffret.manon@gmail.com

Sophie Drapier

Marc Vérin

New tricks for an old dog: a repurposing approach of apomorphine

Keywords: apomorphine, repurposing, neurodegenerative diseases, sexual disorders, neuroleptic malignant syndrome, cancer

Apomorphine is a 150-year old nonspecific dopaminergic agonist, currently indicated for treating motor fluctuations in Parkinson's disease. At the era of drug repurposing, its pleiotropic biological functions suggest other possible uses. To further explore new therapeutic and diagnostic applications, the available literature up to July 2018 was reviewed using the PubMed and Google Scholar databases. As many of the retrieved articles consisted of case reports and preclinical studies, we adopted a descriptive approach, tackling each area of research in turn, to give a broad overview of the potential of apomorphine. Apomorphine may play a role in neurological diseases like restless legs syndrome, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease and disorders of consciousness, but also in sexual disorders, neuroleptic malignant(-like) syndrome and cancer. Further work is needed in both basic and clinical research; current developments in novel delivery strategies and apomorphine derivatives are expected to open the way.

Introduction

« [La thérapeutique médicale] a même, à notre avis, dans ses louables efforts, dépassé le but, en encombrant la science d'une multitude de médicaments nouveaux, qui ont eu l'inconvénient de faire oublier que, parmi les anciens, et parmi les vieilles médications surtout, il y en a qui ont, depuis longtemps, fait leurs preuves et qui ne demandent qu'à être mieux étudiés, soit au laboratoire, soit à la clinique ». 1 Dr Louis Guinard, 1898 Drug repurposing can be defined as the process of identifying new therapeutic opportunities for existing drugs [START_REF] Mehndiratta | Drug repositioning[END_REF][START_REF] Corsello | The Drug Repurposing Hub: a nextgeneration drug library and information resource[END_REF]. Either drug-centered, disease-centered or target-centered, the repurposing approach is an efficient, accelerated and cost-effective way of fulfilling unmet medical needs and a promising alternative to the costly de novo drug discovery and development [START_REF] Montorsi | Apomorphine to Uprima: the development of a practical erectogenic drug: a personal perspective[END_REF][START_REF] Mehndiratta | Drug repositioning[END_REF]. If past repurposing successes have been largely the result of serendipity, large-scale efforts and systematic screening of approved and/or abandoned drugs are now conducted, with the help of bioinformatics [START_REF] Corsello | The Drug Repurposing Hub: a nextgeneration drug library and information resource[END_REF]. According to Nobel-prized Sir James Whyte Black 2 , old drugs are a "fruitful basis for the discovery of a new drug" [START_REF] Raju | The Nobel chronicles[END_REF]. Now off patent, apomorphine was first synthesized in 1845, making it the oldest antiparkinsonian drug. Its clinical use dates back to 1869 and the work of Dr Samuel Jones Gee, who introduced it into the therapeutic armamentarium as a powerful emetic (Auffret et al, 2018a). Following this experimental discovery, apomorphine was empirically used for a multitude of indications, ranging from antipoisoning to expectoration (Auffret et al, 2018a). The discovery of its dopaminergic mechanism of action, along with the synthesis of domperidone (a peripheral dopaminergic antagonist), prompted its rational use as an antiparkinsonian drug at the end of the 1980's (Auffret et al, 2018a). This target-centered approach of a drug previously known as an emetic can therefore be considered as the first major repositioning of apomorphine.

However, the rich empirical history, complex pharmacological profile and pleiotropic biological functions of this 150-year old drug [START_REF] Ribarič | The pharmacological properties and therapeutic use of apomorphine[END_REF]Auffret et al, 2018b) suggest further therapeutic and diagnostic applications.

To investigate its full potential, we conducted a review of the available French and English literature up to July 2018, using the PubMed and Google Scholar databases. Reference lists from relevant studies were screened for additional references. As many of the retrieved articles consisted of case reports and preclinical studies, we adopted a descriptive approach, tackling each area of research in turn and compiling clinical data with recent neuromolecular probes. The search identified several potential repurposing opportunities for apomorphine: restless legs syndrome, Huntington's disease, disorders of consciousness, amyotrophic lateral sclerosis, Alzheimer's disease, erectile dysfunction, female sexual disorder, neuroleptic malignant(-like) syndrome and cancer. Both descriptive and critical, this work aims at giving a broad overview of the potential of apomorphine, to guide basic and clinical research. Proposed mode and sites of action, as well as references of these possible new indications are displayed in Table 1.

Table 1:

Pharmacological targets of apomorphine

Apomorphine (C 17 H 17 NO 2 ) is an aporphine alkaloid derived from morphine, with a number of pharmacological targets, excluding opioid receptors [START_REF] Ribarič | The pharmacological properties and therapeutic use of apomorphine[END_REF][START_REF] Schulze | Apomorphine is a bimodal modulator of TRPA1 channels[END_REF]Auffret et al, 2018b).

The mechanistic underpinning its pleiotropic biological functions is both dopaminergic and non-dopaminergic [START_REF] Ribarič | The pharmacological properties and therapeutic use of apomorphine[END_REF]Auffret et al, 2018b). The semirigid and polycyclic structure (Fig. 1) accounts for the dopaminergic activity (catechol moiety) and the rapid crossing of the blood-brain-barrier (lipophilicity). The chiral center of the dopamine moiety (6-a, Fig. 1) results in two enantiomers, namely R-(-)-apomorphine (currently used in therapeutics) and S-(+)-apomorphine (Fig. 1, with the same chemical structure but different pharmacological profiles (Auffret et al, 2018b).

S-(+)-apomorphine is a dopaminergic antagonist (dopamine D 1 -like and D 2 -like receptors) and a serotonergic antagonist (serotonergic 5-HT3 receptor) whereas R-(-)-apomorphine acts as an agonist on every subtypes of dopaminergic receptors (with variable affinities and a biphasic effect) and as a partial agonist at the serotonergic 5-HT 3 receptor [START_REF] Goldman | Aporphine enantiomers. Interactions with D-1 and D-2 dopamine receptors[END_REF][START_REF] Ribarič | The pharmacological properties and therapeutic use of apomorphine[END_REF]Auffret et al, 2018a). R-(-)-apomorphine has been used as a neuroendocrine probe of central dopaminergic activity in various disorders (e.g Parkinson's disease -PD, psychiatric disorders, addictions), with measurement of prolactin and growth hormone (GH) levels before and after apomorphine administration [START_REF] Friess | Increased growth hormone response to apomorphine in Parkinson disease compared with multiple system atrophy[END_REF][START_REF] Guardia | The apomorphine test: a biological marker for heroin dependence disorder?[END_REF][START_REF] Brunerova | Sublingual apomorphine as a neuroendocrine probe[END_REF]Auffret et al, 2018b). Though poorly explored, R-(-)-apomorphine also acts on the serotonergic and adrenergic systems [START_REF] Ribarič | The pharmacological properties and therapeutic use of apomorphine[END_REF]Auffret et al, 2018b). Human transient receptor potential A (TRPA1) is also modulated by R-(-)apomorphine, suggesting a role in sensory processes, with low doses inducing irreversible activation, and high doses causing a reduction of single-channel open times [START_REF] Schulze | Apomorphine is a bimodal modulator of TRPA1 channels[END_REF]. In vitro, ex vivo and in vivo studies have also shown that R-(-)-and S-(+)-apomorphine display both neuroprotection and neurotoxicity through several mechanisms [START_REF] Guo | Apomorphine induces trophic factors that support fetal rat mesencephalic dopaminergic neurons in cultures[END_REF]Kyriasis, 2003;[START_REF] Yuan | Neuroprotective and neurotrophic effect of apomorphine in the striatal 6-OHDA-lesion rat model of Parkinson's disease[END_REF][START_REF] Picada | Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine[END_REF]Auffret et al, 2018b).

They involve trophic factor induction (BDNF [START_REF] Guo | Apomorphine induces trophic factors that support fetal rat mesencephalic dopaminergic neurons in cultures[END_REF]FGF-2 Li et al, 2006;GDNF Ohta et al, 2000[START_REF] Guo | Apomorphine induces trophic factors that support fetal rat mesencephalic dopaminergic neurons in cultures[END_REF]NGF Ohta et al, 2000), radical scavenging [START_REF] Ubeda | Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines[END_REF][START_REF] Hara | Apomorphine protects against 6-hydroxydopamine-induced neuronal cell death through activation of the Nrf2-ARE pathway[END_REF], metal scavenging [START_REF] Ubeda | Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines[END_REF]Youdim et al, 1999), oxidant and antioxidant activity [START_REF] Ubeda | Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines[END_REF][START_REF] Gassen | Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction[END_REF][START_REF] Gassen | Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine[END_REF][START_REF] Grünblatt | Potent neuroprotective and antioxidant activity of apomorphine in MPTP and 6-hydroxydopamine induced neurotoxicity[END_REF]Grünblatt et al, , 1999b[START_REF] Grünblatt | Effects of R-and S-apomorphine on MPTP-induced nigro-striatal dopamine neuronal loss[END_REF]dos Santos El Bacha et al 2001;[START_REF] Auffret | Continuous subcutaneous infusion of apomorphine rescues nigro-striatal dopaminergic terminals following MPTP injection in mice[END_REF]Kyriasis, 2003;[START_REF] Pardini | Dose-dependent induction of apoptosis by R-apomorphine in CHO-K1 cell line in culture[END_REF][START_REF] Mandel | Iron and a-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallate[END_REF];[START_REF] Picada | Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine[END_REF][START_REF] Castri | Protection by apomorphine in two independent models of acute inhibition of oxidative metabolism in rodents[END_REF][START_REF] Hara | Apomorphine protects against 6-hydroxydopamine-induced neuronal cell death through activation of the Nrf2-ARE pathway[END_REF][START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF][START_REF] Ma | Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine[END_REF], activation of anti-inflammatory pathways [START_REF] Hara | Apomorphine protects against 6-hydroxydopamine-induced neuronal cell death through activation of the Nrf2-ARE pathway[END_REF] and apoptosis modulation [START_REF] Gassen | Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction[END_REF][START_REF] Pardini | Dose-dependent induction of apoptosis by R-apomorphine in CHO-K1 cell line in culture[END_REF], Ma et al, 2011). Depending on the dose, duration and cell types, apomorphine can therefore be cytoprotective, cytostatic or even cytotoxic. Finally, R-(-)-and S-(+)apomorphine inhibit the monoamine oxidase A and B, as well as the tyrosine hydroxylase [START_REF] Grünblatt | Effects of R-and S-apomorphine on MPTP-induced nigro-striatal dopamine neuronal loss[END_REF]Auffret et al, 2018b) Apomorphine acts on dopaminergic pathways, which makes it an interesting candidate in the treatment of dopaminergic disorders, such as Parkinson's disease (PD), but also restless legs syndrome, neuroleptic(-like) malignant syndrome or sexual disorders. Its potential role in counteracting neuroinflammation and oxidative stress could be critical in the pathogenesis of many neurological disorders, including PD, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) or Huntington's disease (HD). Finally, its modulation of apoptosis makes it a good candidate for future cancer therapies.

Apomorphine and neurological diseases

Apomorphine was first associated with choreic movements at the end of the XIX th century, with the work of Pierce (1870) and Edmond Weill (1884) (Auffret et al, 2018a). It is currently indicated for parkinsonian motor fluctuations resistant to oral treatment. Though still underused, its interest in PD extends beyond motor disorders, with new data emerging on its efficacy on nonmotor symptoms and its potential value when administered earlier in the course of the disease (Auffret et al, 2018a,b). Its rapid onset, short duration of action, way of administration (subcutaneous and acute vs chronic) and pleiotropic biological functions point out towards various other uses in neurological diseases, supported by preclinical data (AD, ALS) and clinical studies (RLS, HD, disorders of consciousness).

Restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS)

RLS is a common sensorimotor disorder associated with brain iron deficiency, neurotransmission abnormalities in the dopaminergic (D 2 -receptors) and opiate systems, and abnormal activity in a distributed cortical and subcortical network [START_REF] Mano | Anatomo-functional basis of restless legs syndrome[END_REF]. The fact that the apomorphine challenge (0.005 mg/kg of body weight) does not induce a GH increase in RLS patients (contrary to PD) support the hypothesis that RLS is not solely a dopaminergic disorder [START_REF] Happe | Growth hormone response to low-dose apomorphine in restless legs syndrome[END_REF]. Either primary (familial) or secondary (druginduced, uraemia, iron deficiency), RLS appears to be more prevalent in neurodegenerative diseases such as PD and multiple system atrophy (MSA) [START_REF] Reuter | Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome[END_REF][START_REF] Tribl | Apomorphine in idiopathic restless legs syndrome: an exploratory study[END_REF][START_REF] Tings | Treatment of restless legs syndrome with subcutaneous apomorphine in a patient with short bowel syndrome[END_REF][START_REF] Ghorayeb | Restless legs syndrome in multiple system atrophy[END_REF]. Leg paresthesias and/or dysesthesias, occurring at rest, causing an urge to move, are characteristics, and usually relieved by movement [START_REF] Happe | Growth hormone response to low-dose apomorphine in restless legs syndrome[END_REF][START_REF] Mano | Anatomo-functional basis of restless legs syndrome[END_REF]. Symptoms often worsen at night and negatively affect sleep and quality of life [START_REF] Happe | Growth hormone response to low-dose apomorphine in restless legs syndrome[END_REF]. Abnormal periodic legs/limbs movements during wakefulness (PLMW) or sleep (PLMS), consisting of episodes of stereotyped limb movements, are commonly associated with RLS [START_REF] Paradiso | Effects of apomorphine on flexor reflex and periodic limb movement[END_REF][START_REF] Haba-Rubio | Acute low single dose of apomorphine reduces periodic limb movements but has no significant effect on sleep arousals: a preliminary report[END_REF][START_REF] Tribl | Apomorphine in idiopathic restless legs syndrome: an exploratory study[END_REF][START_REF] Happe | Growth hormone response to low-dose apomorphine in restless legs syndrome[END_REF]. In a recent evidence-based review examining current treatment for RLS, levodopa and a few dopaminergic agonists (ropinirole, rotigotine, cabergoline, pramipexole) were deemed "efficacious at an acceptable risk", with special monitoring [START_REF] Winkelmann | Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017) §[END_REF]. Apomorphine was not mentioned in this review. However, five case reports [START_REF] Reuter | Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome[END_REF]Haba-Rubio et al, 2002;[START_REF] Paradiso | Effects of apomorphine on flexor reflex and periodic limb movement[END_REF][START_REF] Tings | Treatment of restless legs syndrome with subcutaneous apomorphine in a patient with short bowel syndrome[END_REF][START_REF] Müller | Continuous Subcutaneous Apomorphine Infusion Improves Severe Restless Legs Syndrome[END_REF] and one cases series [START_REF] Tribl | Apomorphine in idiopathic restless legs syndrome: an exploratory study[END_REF] support its potential interest in treating RLS and/or PLMS, either through acute injections or continuous infusion. Nocturnal apomorphine infusion was evaluated in two RLS patients (46 and 58 years, idiopathic RLS and RLS secondary to PD) with PLMS (not assessed during the study) and nocturnal symptoms refractory to conventional oral therapy, with one double-blind trial with placebo [START_REF] Reuter | Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome[END_REF]. Overnight monotherapy (12 mg and 18 mg) led to a significant reduction in nocturnal discomfort and leg movements, as well as an improvement in pain and spasm scores [START_REF] Reuter | Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome[END_REF]. Both patients continued nocturnal apomorphine infusion after discharge and reported a persistent benefit on sleep, as well as an improvement in daily living activities during the mean follow-up of 12 months [START_REF] Reuter | Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome[END_REF]. In another study [START_REF] Tings | Treatment of restless legs syndrome with subcutaneous apomorphine in a patient with short bowel syndrome[END_REF], a 38-year old female patient with short bowel syndrome and uncontrollable uraemic RLS was successfully treated by subcutaneous (SC) injections of apomorphine (1 mg) administered at nighttime and before each hemodialysis. RLS symptoms were reduced (IRLSRS 3 score) and concomitant treatment (fentanyl and pirtramid) tapered off. After six months, the patient remained stable, with one or two selfinjections per day. A prospective and open-label study evaluated the efficacy of apomorphine in nine consecutive patients (5 male, mean age 55.3 years) with severe idiopathic RLS [START_REF] Tribl | Apomorphine in idiopathic restless legs syndrome: an exploratory study[END_REF]. Apomorphine was first administered as a bolus (0.035 mg/kg body weight) and then continuously (intravenous (IV) infusion of 0.03 mg/kg/h, adjusted by 0.01 mg/kg/h increments until stable clinical effect). A rapid and significant reduction in subjective leg symptoms (mean latency of 13. 1 min), as well as PLM during wakefulness (mean latency of 5.1 min) were observed. These effects were not antagonized by naloxone. Drowsiness, yawning, dizziness and nausea were the main reported side effects. However, the IV route is not recommended for apomorphine, due to crystal accumulation and hazardous IV thrombotic complications [START_REF] Manson | Intravenous apomorphine therapy in Parkinson's disease: clinical and pharmacokinetic observations[END_REF]. Similarly, a persistent ( 6months follow-up) beneficial effect of continuous subcutaneous apomorphine infusion therapy (CSAI, 120 mg/day) was reported in an 80-year old patient suffering from RLS and polyneuropathy, without severe side effects [START_REF] Müller | Continuous Subcutaneous Apomorphine Infusion Improves Severe Restless Legs Syndrome[END_REF]. Haba-Rubio and colleagues studied the effect of an acute low single dose of apomorphine (0.5mg) in nine patients (three men, mean age 49.5 years) with PLMS, including eight with RLS [START_REF] Haba-Rubio | Acute low single dose of apomorphine reduces periodic limb movements but has no significant effect on sleep arousals: a preliminary report[END_REF]. The number of PLMS decreased during the first 4h following apomorphine injection.

Finally, PLM and flexor reflex decreased 10 min after the SC administration of 3 mg of apomorphine in a 65year old man, and completely disappeared after 30 min [START_REF] Paradiso | Effects of apomorphine on flexor reflex and periodic limb movement[END_REF]. These encouraging preliminary data support the use of apomorphine (associated with domperidone) as a second-line therapy in patients who failed to respond to conventional RLS drug regimen [START_REF] Tings | Treatment of restless legs syndrome with subcutaneous apomorphine in a patient with short bowel syndrome[END_REF][START_REF] Tribl | Apomorphine in idiopathic restless legs syndrome: an exploratory study[END_REF][START_REF] Müller | Continuous Subcutaneous Apomorphine Infusion Improves Severe Restless Legs Syndrome[END_REF].

Similarly to PD, interindividual dose variability is reported [START_REF] Tribl | Apomorphine in idiopathic restless legs syndrome: an exploratory study[END_REF] and suggest that apomorphine treatment must be tailored to each case. In addition, as suggested by Tribl and colleagues, a "modified apomorphine test" could be considered as a diagnosis tool in RLS, using visual analogue scale and/or suggested immobilization test [START_REF] Tribl | Apomorphine in idiopathic restless legs syndrome: an exploratory study[END_REF]. Dysfunction of central dopaminergic pathways are also described, with biphasic changes [START_REF] Cepeda | The role of dopamine in Huntington's disease[END_REF][START_REF] Schwab | Dopamine and Huntington's disease[END_REF]: in early stages, dopamine neurotransmission is enhanced, leading to hyperkinetic movements, whereas late stages are more characterized by dopaminergic deficits [START_REF] Cepeda | The role of dopamine in Huntington's disease[END_REF]. As quality of life is profoundly affected, management involves a combination of pharmacological and non-pharmacological interventions [START_REF] Vitale | Short-term continuous infusion of apomorphine hydrochloride for treatment of Huntington's chorea: A double blind, randomized crossover trial[END_REF][START_REF] Mccolgan | Huntington's disease: a clinical review[END_REF][START_REF] Kieburtz | Huntington's disease: Current and future therapeutic prospects[END_REF]. Promising preclinical approaches targeting excitotoxicity, mitochondrial dysfunction or inflammation have failed to show efficacy in clinical trials [START_REF] Kieburtz | Huntington's disease: Current and future therapeutic prospects[END_REF]) and, to date, no therapy can meaningfully control nor prevent HD devastating evolution [START_REF] Mccolgan | Huntington's disease: a clinical review[END_REF][START_REF] Kieburtz | Huntington's disease: Current and future therapeutic prospects[END_REF]. Gene-directed therapies appears to be one of the most promising approach currently investigated [START_REF] Cepeda | The role of dopamine in Huntington's disease[END_REF][START_REF] Kieburtz | Huntington's disease: Current and future therapeutic prospects[END_REF]. However, within a shorter timeline, targeting dopaminergic abnormalities and glutamate receptor dysfunction also seems to be a good strategy [START_REF] Cepeda | The role of dopamine in Huntington's disease[END_REF][START_REF] Schwab | Dopamine and Huntington's disease[END_REF]. Potential dopaminergic treatments have therefore been tested in clinical trials, with variable success on choreic movements and motor function [START_REF] Schwab | Dopamine and Huntington's disease[END_REF]. A limited number of reports on the use of apomorphine in HD are scattered through the literature. Patients' characteristics and apomorphine parameters are summarized in Table 2. Tolosa & Sparber were the first to report that SC administration of at least 1 mg of apomorphine resulted in a transient but significant reduction of abnormal involuntary movements in HD patients (N=4), within 10 to 20 min and for up to 80 min [START_REF] Tolosa | Apomorphine in Huntington's chorea: clinical observations and theoretical considerations[END_REF]. If these results were in contrast with a previous study from [START_REF] Lal | Apomorphine, pimozide, L-Dopa and the probenecid test in Huntington's chorea[END_REF] (where acute injections of 1mg of apomorphine were deprived of any effect in two HD patients), they were reproduced a few years later (Table 2) [START_REF] Corsini | Apomorphine hydrochloride-induced improvement in Huntington's chorea: stimulation of dopamine receptor[END_REF][START_REF] Caraceni | Effects of DA agonist in Huntington disease hyperkinesia[END_REF][START_REF] Bentivoglio | Apomorphine injections acutely improve chorea in patients with Huntington's disease[END_REF][START_REF] Albanese | Acute challenge with apomorphine in Huntington's disease: a double-blind study[END_REF]. The amplitude and frequency of choreic movements appears to be reduced in a dose-related way [START_REF] Corsini | Apomorphine hydrochloride-induced improvement in Huntington's chorea: stimulation of dopamine receptor[END_REF][START_REF] Caraceni | Effects of DA agonist in Huntington disease hyperkinesia[END_REF], and the transiency of the antichoreic effect reflects the short half-life of apomorphine [START_REF] Vitale | Short-term continuous infusion of apomorphine hydrochloride for treatment of Huntington's chorea: A double blind, randomized crossover trial[END_REF]Auffret et al, 2018b). To be noted, apomorphine antichoreic effect could be antagonized partially by 2mg of haloperidol and completely by 100 mg of sulpiride, hence supporting the hypothesis that it is mediated by dopaminergic receptors [START_REF] Tolosa | Apomorphine in Huntington's chorea: clinical observations and theoretical considerations[END_REF][START_REF] Corsini | Apomorphine hydrochloride-induced improvement in Huntington's chorea: stimulation of dopamine receptor[END_REF]. It has been suggested that the effect of apomorphine on abnormal involuntary movements was partly due to its sedative and hypnotic action [START_REF] Caraceni | Effects of DA agonist in Huntington disease hyperkinesia[END_REF][START_REF] Albanese | Acute challenge with apomorphine in Huntington's disease: a double-blind study[END_REF], but this seems unlikely [START_REF] Tolosa | Apomorphine in Huntington's chorea: clinical observations and theoretical considerations[END_REF][START_REF] Corsini | Apomorphine hydrochloride-induced improvement in Huntington's chorea: stimulation of dopamine receptor[END_REF][START_REF] Sanberg | Sedative effects of apomorphine in an animal model of Huntington's disease[END_REF]. Based on their results, Albanese and collaborators suggested that HD patients could benefit from chronic and tailored treatment with dopaminergic agonists [START_REF] Albanese | Acute challenge with apomorphine in Huntington's disease: a double-blind study[END_REF]. This hypothesis was tested in a pilot, single center, double blind, randomized, crossover and controlled versus placebo trial [START_REF] Vitale | Short-term continuous infusion of apomorphine hydrochloride for treatment of Huntington's chorea: A double blind, randomized crossover trial[END_REF]. Nine unrelated consecutive HD patients underwent an apomorphine test to determine the most efficient dose; four patients were withdrawn from the study due to lack (N=2) or worsening (N=2) of response [START_REF] Vitale | Short-term continuous infusion of apomorphine hydrochloride for treatment of Huntington's chorea: A double blind, randomized crossover trial[END_REF]. Compared to placebo, CSAI (5 day-time regimen, 12 h/day, 10 to 20µg/kg body weight) produced a significant and sustained benefit on choreic symptoms, with a very satisfying safety and tolerability profile [START_REF] Vitale | Short-term continuous infusion of apomorphine hydrochloride for treatment of Huntington's chorea: A double blind, randomized crossover trial[END_REF]. Taken together, these data suggest that apomorphine is of interest in HD, after preliminary screening to detect non-responders. It is quite surprising that large studies exploring the longterm efficacy of CSAI in HD have not been conducted yet.

Huntington's disease

Disorders of consciousness

Though still incompletely understood, the neuropathology of traumatic brain injury (TBI) involve direct anatomical damage (primary injury) and disruption of both functional electrical and chemical transmission [START_REF] Pistoia | Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?[END_REF][START_REF] Chen | Impact of Traumatic Brain Injury on Dopaminergic Transmission[END_REF]. This "secondary phase", evolving for weeks and even months after the mechanical injury (diffuse axonal injury) is characterized by persistent neuroinflammation, oxidative stress, neurotrophic factors changes and apoptosis of neurons and glia [START_REF] Chen | Impact of Traumatic Brain Injury on Dopaminergic Transmission[END_REF]. TBI can induce long-term disorders of consciousness (DOC), including vegetative state (VS) and minimally conscious state (MCS), characterized by arousal but lack of awareness [START_REF] Pistoia | Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?[END_REF]. VS and MCS (to a lesser extent) stem from a disconnection of several cortical networks associated with functional changes at the neurotransmitter level [START_REF] Pistoia | Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?[END_REF][START_REF] Chen | Impact of Traumatic Brain Injury on Dopaminergic Transmission[END_REF]. More precisely, alterations in monoamine signaling and dopaminergic abnormalities (in the nigrostriatal and mesolimbic systems) are documented in a significant proportion of patients suffering from moderate to severe TBI [START_REF] Fridman | Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury[END_REF][START_REF] Chen | Impact of Traumatic Brain Injury on Dopaminergic Transmission[END_REF]. Therapeutic goals open-label pilot study [START_REF] Fridman | Fast awakening from minimally conscious state with apomorphine[END_REF]2010). Before apomorphine initiation, patients were administered domperidone (20 mg three times a day) to circumvent peripheral side effects. Apomorphine was initiated at an infusion rate of 2 mg/h for 12 h per day, up to 8mg/h for 12 to 16h per day. Levels of consciousness were objectified through the Coma Near-Coma Scale (CNCS) and the Disability Rating Scale (DRS). Results are summarized in Table 3. All patients began to respond to commands after initiation of apomorphine treatment, within 10 days (N=4) or above 4 weeks (N=4) (1-62 days). All surviving patients (N=7) reached a CNCS of 0 within a year and returned home, with moderate disability or good recovery. Four patients reached an independent walking ability and two regained full independence. Side effects were mild to moderate and included local reactions, sedation, agitation, drowsiness, nausea and vomiting [START_REF] Fridman | Fast awakening from minimally conscious state with apomorphine[END_REF]2010). Some patients experienced dyskinesia at the highest dose of apomorphine (8 mg/h) [START_REF] Fridman | Fast awakening from minimally conscious state with apomorphine[END_REF]2010). Of major interest, improvements were maintained in all patients after apomorphine discontinuation. CSAI therefore seems to be a feasible and safe way to achieve a sustained functional recovery [START_REF] Fridman | Fast awakening from minimally conscious state with apomorphine[END_REF]2010). To be noted, seven patients had been previously and unsuccessfully treated with dopaminergic stimulants, which points out towards non-dopaminergic mechanisms, like neurotrophic factors induction or neurorecovery properties [START_REF] Guo | Apomorphine induces trophic factors that support fetal rat mesencephalic dopaminergic neurons in cultures[END_REF] -but that remains to be proven.

(
Nevertheless, these results are not based on a rigorous double-blind placebo-controlled design and are only confined to a few subjects. Larger samples are needed, especially since patients' heterogeneity regarding injuries, extent of lesion and management, make interpretation difficult [START_REF] Pistoia | Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?[END_REF][START_REF] Chen | Impact of Traumatic Brain Injury on Dopaminergic Transmission[END_REF]. A prospective, multi-center, randomized, double-blind, placebo-controlled study of the safety and efficacy of apomorphine hydrochloride (NH001, up to 6 mg/h for 12 h a day) in VS and MCS following TBI was launched in 2010 and expected to enroll 76 patients (ClinicalTrials.gov Identifier: NCT00761228), but it is currently suspended 4 . Further studies involving neuroimaging and/or electroencephalography source connectivity [START_REF] Hassan | EEG source connectivity analysis: from dense array recordings to brain networks[END_REF] should be conducted to confirm these preliminary findings and to assert which type(s) of DOC patients are more likely to benefit from apomorphine therapy.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rare (2 to 3 cases per 100 000 individuals) progressive neurodegenerative disease, affecting upper and lower motor neurons and leading to loss of muscle function and paralysis [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF]. Cognitive and behavioral impairment are often associated with motor dysfunction [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF]. The etiology of ALS remains poorly understood but an association between genetic risk and environmental factors is suspected [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF]. The neuropathological hallmark of ALS is the presence of protein aggregates in motor neurons, either TDP43 or misfolded SOD-1 (superoxide dismutase) [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF]. Neuroinflammation, mitochondrial dysfunction, excitotoxicity and oligodendrocytes degeneration are also observed [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF]. SOD-1-related toxicity include hyperexcitability, glial dysfunction and oxidative stress (Da [START_REF] Costa | A new zebrafish model produced by TILLING of SOD1-related amyotrophic lateral sclerosis replicates key features of the disease and represents a tool for in vivo therapeutic screening[END_REF][START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF].

Management strategies mostly rely on developing disease-modifying therapy and symptomatic treatment [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF], and effective antioxidant therapies are not available yet for ALS [START_REF] Mead | S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis Free[END_REF].

Future treatments are expected to target specific disease subtypes, through a personalized approach [START_REF] Hardiman | Amyotrophic lateral sclerosis[END_REF]).

An orphan drug designation for S-(+)-apomorphine was granted in February 2012 by the European

Medicines regulatory agency (EU/3/12/954 5 ) to the University of Sheffield (United Kingdom) for the treatment of ALS. Recent preclinical data [START_REF] Mead | S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis Free[END_REF][START_REF] Costa | A new zebrafish model produced by TILLING of SOD1-related amyotrophic lateral sclerosis replicates key features of the disease and represents a tool for in vivo therapeutic screening[END_REF] have indeed shown that S-(+)apomorphine is a CNS-penetrant Nrf2 activator [START_REF] Mead | S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis Free[END_REF]) and a potential antioxidant both in vitro [START_REF] Sam | Free radical scavenging properties of apomorphine enantiomers and dopamine: possible implication in their mechanism of action in parkinsonism[END_REF][START_REF] Gassen | Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine[END_REF] and in vivo (mice, zebrafish embryos) [START_REF] Mead | S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis Free[END_REF][START_REF] Costa | A new zebrafish model produced by TILLING of SOD1-related amyotrophic lateral sclerosis replicates key features of the disease and represents a tool for in vivo therapeutic screening[END_REF]. S-(+)-apomorphine reduces pathological oxidative stress and improve survival of fibroblasts from both sporadic and familial ALS patients who harbor SOD1 mutations [START_REF] Mead | S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis Free[END_REF]. In addition, S-(+)apomorphine significantly attenuates motor dysfunction in the G93A SOD1 transgenic mouse model of ALS (though without improving survival) and increases survival in the T70I sod1 zebrafish model (G93Ros10-Sh4 line) [START_REF] Mead | S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis Free[END_REF][START_REF] Costa | A new zebrafish model produced by TILLING of SOD1-related amyotrophic lateral sclerosis replicates key features of the disease and represents a tool for in vivo therapeutic screening[END_REF]. Data are still scarce and, at the time of our writing, clinical trials with S-(+)-apomorphine in patients with ALS have not started. Nonetheless, these preliminary results are encouraging and call for further investigation. To be noted, R-(-)-apomorphine is a glutaminase inhibitor [START_REF] Thomas | Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors[END_REF]; it would be interesting to investigate whether S-(+)-apomorphine has the same activity, and acts on glutamate-induced excitotoxicity, a known component of corticomotor neuronal hyperexcitability [START_REF] Yuan | Cell Death-Autophagy Loop and Glutamate-Glutamine Cycle in Amyotrophic Lateral Sclerosis[END_REF].

Alzheimer's disease

Alzheimer's disease (AD) is a chronic and progressive disease characterized by central (dementia), peripheral (cardiovascular, hepatic, respiratory disorders) and systemic (disorders of systemic immunity, microbiota disturbance, systemic inflammation) abnormalities [START_REF] Wang | A systemic view of Alzheimer disease -insights from amyloid-β metabolism beyond the brain[END_REF]. Either sporadic or genetic, AD is currently untreatable and effective treatments (either preventive or curative) are lacking, despite hundreds of clinical trials [START_REF] Ohyagi | Apomorphine: A Novel Efficacy for Alzheimer's Disease and Its Mechanisms[END_REF][START_REF] Wang | A systemic view of Alzheimer disease -insights from amyloid-β metabolism beyond the brain[END_REF][START_REF] Nakamura | Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease[END_REF]. Current pharmacological management is based on cognition-enhancing agents (cholinesterase inhibitors and NMDA receptor antagonist), with limited efficacy [START_REF] Masters | Alzheimer's disease[END_REF]. The two major hallmarks of AD are senile plaques, caused by abnormal amyloid-β (Aβ) metabolism, and neurofibrillary tangles (aggregates of hyperphosphorylated tau proteins), which spread through the brain as the disease progresses [START_REF] Masters | Alzheimer's disease[END_REF][START_REF] Wang | A systemic view of Alzheimer disease -insights from amyloid-β metabolism beyond the brain[END_REF]. Other mechanisms are also involved in AD pathogenesis, including but not limited to oxidative stress (enhancing protein aggregation), (micro)glial changes and reactivity, increased insulin resistance and neuroinflammation [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF][START_REF] Ohyagi | Apomorphine: A Novel Efficacy for Alzheimer's Disease and Its Mechanisms[END_REF][START_REF] Wang | A systemic view of Alzheimer disease -insights from amyloid-β metabolism beyond the brain[END_REF][START_REF] Nakamura | Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease[END_REF]. For the last few years, Aβ has been a fertile area of http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2012/03/human_orphan_ 001028.jsp&mid=WC0b01ac058001d12b

research, owing to the fact that an imbalance between the production and elimination of Aβ is found very early in the disease and precedes the occurrence of neurofibrillary tangles [START_REF] Lashuel | New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease[END_REF][START_REF] Ohyagi | Apomorphine: A Novel Efficacy for Alzheimer's Disease and Its Mechanisms[END_REF][START_REF] Masters | Alzheimer's disease[END_REF][START_REF] Wang | A systemic view of Alzheimer disease -insights from amyloid-β metabolism beyond the brain[END_REF]. Aβ is divided into several types, including Aβ40 but also Aβ42, considered as an important therapeutic target, due to its neurotoxicity and early appearance [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF][START_REF] Ohyagi | Apomorphine: A Novel Efficacy for Alzheimer's Disease and Its Mechanisms[END_REF][START_REF] Nakamura | Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease[END_REF]. R-(-)-apomorphine and apomorphine derivatives (R-(-)-norapomorphine) interfere with the mechanisms of fibrillization (Aβ1-40) and/or oligomerization (Aβ42) [START_REF] Lashuel | New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease[END_REF][START_REF] Hanaki | Mechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine[END_REF]. The hydrophobic nature of apomorphine may increase its affinity for binding Aβ, but other mechanisms may account for this activity [START_REF] Steele | Apomorphine and Alzheimer Aβ: roles for regulated α cleavage, autophagy, and antioxidation?[END_REF], including the autoxidation of the 10,11-dihidroxy substitutions of the phenol ring [START_REF] Lashuel | New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease[END_REF][START_REF] Hanaki | Mechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine[END_REF]. In addition, R-(-)-apomorphine enhances degradation of intracellular Aβ42 in human neuroblastoma cells (SH-SY5Y) [START_REF] Hanaki | Mechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine[END_REF] and in the familial triple transgenic AD mouse model (3xTg-AD mice) [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF]. The promotion of intracellular Aβ degradation seems to be mediated through Aβ-degrading enzymes, proteasome and insulindegrading enzyme (IDE) [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF]. Apomorphine also decreased hyperphosphorylated tau proteins levels and protected neurons from oxidative stress in the same AD mice model [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF].

Apomorphine was also shown to reduce oxidative stress in 3xTg-AD mice, as well as in a human neuroblastoma cell line (SH-SY5Y), by targeting p53-related apoptosis and enhancing glutathione peroxidase (GPx) activity, among other possible mechanisms [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF][START_REF] Ma | Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine[END_REF]. These effects were not limited to intracellular changes: when administered subcutaneously to 3xTg-AD mice once a week for one month (5-20 mg/kg), apomorphine even improved short-term memory function, the best results being obtained with a dose of 5mg/kg [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF]. Very recently, another study showed that 1-month SC injections of R-(-)apomorphine to 3xTg-AD mice (6 and 12 months of age) decreased brain insulin resistance (upregulation of insulin-degrading enzyme) and improved spatial memory [START_REF] Nakamura | Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease[END_REF]. These preliminary results

(apparent anti-amyloidogenic, neuroprotective and antioxidant properties) suggest that apomorphine (or apomorphine derivatives, [START_REF] Lashuel | New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease[END_REF][START_REF] Nabavi | Aporphines and Alzheimer's disease: Towards a Medical Approach Facing the Future[END_REF] therapy could be beneficial in AD [START_REF] Lashuel | New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease[END_REF][START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF], either early in the disease [START_REF] Lashuel | New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease[END_REF][START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF] or in advanced stages [START_REF] Nakamura | Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease[END_REF]. Another argument is that antemortem apomorphine exposure was found to significantly reduce Aβ deposition (diffuse and total plaque load) in the brain of cognitively normal parkinsonian donors (N=19), compared to those who were never exposed to apomorphine (N=17) [START_REF] Yarnall | The pivotal role of iron in NF-kappa B activation and nigrostriatal dopaminergic neurodegeneration. Prospects for neuroprotection in Parkinson's disease with iron chelators[END_REF]. In contrast to AD murine model [START_REF] Himeno | Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation[END_REF]) however, no difference was observed after apomorphine exposure in tau aggregation in the PD brains [START_REF] Yarnall | The pivotal role of iron in NF-kappa B activation and nigrostriatal dopaminergic neurodegeneration. Prospects for neuroprotection in Parkinson's disease with iron chelators[END_REF].

Further work is needed to determine whether apomorphine has a modifying effect on Aβ deposition in AD, and to assess the best time for initiating therapy. A small-sized (N=5) pilot clinical trial exploring the efficacy of a weekly injection of Apokyn® in AD patients apparently showed that memory function improved after 3 months of treatment, which is promising [START_REF] Nakamura | Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease[END_REF]. At the time of our writing however, no detailed data on this trial were available.

Apomorphine and sexual disorders

Men

Erectile dysfunction (ED) is the most common sexual complaint in men [START_REF] Albersen | The future is today: emerging drugs for the treatment of erectile dysfunction[END_REF]. This complex and multifactorial disorder [START_REF] Costa | Multidimensional nature of apomorphine SL (Ixense) therapy[END_REF] is defined as a "persistent inability to achieve and/or maintain an erection sufficient for satisfactory sexual intercourse" (NIH Consensus Conference, 1993). As penile erection is regulated both centrally (dopamine and melanocortin-receptors) and peripherally (nitric oxide -NO-and stimulation of smooth muscle relaxation), numerous factors can contribute to ED: endothelial dysfunction (vascular disorders), systemic, psychological and/or neurological disorders, hormonal factors, advancing age and/or iatrogenic causes (MacLennan et al, 2004;[START_REF] Afif-Abdo | Comparative cross-over study of sildenafil and apomorphine for treating erectile dysfunction[END_REF][START_REF] Albersen | The future is today: emerging drugs for the treatment of erectile dysfunction[END_REF][START_REF] Mohee | The evaluation of apomorphine for the treatment of erectile dysfunction[END_REF].

In the beginning of the 1970's, preclinical experiments showed that apomorphine reliably induces several behavioral changes (genital grooming, yawning) and genital responses (penile erections, mounting, intromission and ejaculation) in male rats [START_REF] Butcher | Effects of apomorphine, (+)-amphetamine, and nialamide on tetrabenazineinduced suppression of sexual behavior in the male rat[END_REF][START_REF] Tagliamonte | Aphrodisiac effect of L-DOPA and apomorphine in male sexually sluggish rats[END_REF][START_REF] Heaton | The characterization of a bio-assay of erectile function in a rat model[END_REF][START_REF] Melis | Apomorphine-and oxytocin-induced penile erection and yawning in intact and castrated male rats: effect of sexual steroids[END_REF].

The same effects were reported in "sexually sluggish" rats [START_REF] Tagliamonte | Aphrodisiac effect of L-DOPA and apomorphine in male sexually sluggish rats[END_REF] and in castrated rats in the presence or absence of testosterone, by some authors [START_REF] Malmnäs | Dopaminergic reversal of the decline after castration of rat copulatory behaviour[END_REF][START_REF] Scaletta | Systemic or intracranial apomorphine increases copulation in long-term castrated male rats[END_REF]) whereas others did not reproduce the same results [START_REF] Heaton | Effects of castration and exogenous testosterone supplementation in an animal model of penile erection[END_REF]. These apomorphine-induced sexual effects were partially antagonized by haloperidol, pointing out towards dopaminergic pathways [START_REF] Tagliamonte | Aphrodisiac effect of L-DOPA and apomorphine in male sexually sluggish rats[END_REF].

Since then, apomorphine was shown to act through a central mechanism [START_REF] Review | Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum[END_REF] and a potential additional spinal site of action [START_REF] Ishizuka | Effect of apomorphine on intracavernous pressure and blood pressure in conscious, spinalized rats[END_REF]. Advancing age reduces apomorphine efficacy in rats, presumably through an alteration of central dopaminergic pathways [START_REF] Varrin | Age-related changes in apomorphine-induced erections[END_REF]. Around the same time, clinical trials led to the serendipitous discovery that SC injections of apomorphine (1-4mg) induced spontaneous penile erection in men [START_REF] Lal | Apomorphine and psychopathology[END_REF]. In men, these effects are mediated by a direct activation of the hypothalamic dopaminergic pathways, the central neural paths leading to vasodilatation [START_REF] Melis | Apomorphine-induced penile erection and yawning: site of action in brain[END_REF][START_REF] Melis | Apomorphine-and oxytocin-induced penile erection and yawning in intact and castrated male rats: effect of sexual steroids[END_REF][START_REF] Lal | Apomorphine: clinical studies on erectile impotence and yawning[END_REF][START_REF] Tarcan | Systemic administration of apomorphine improves the hemodynamic mechanism of clitoral and vaginal engorgement in the rabbit[END_REF][START_REF] Maclennan | Examination of the safety and use of apomorphine prescribed in general practice in England as a treatment for erectile dysfunction[END_REF][START_REF] Riley | Inhalation device allows novel administration of apomorphine in men with erectile dysfunction-efficacy and safety findings[END_REF], and a potential peripheral relaxant direct effect on the corpus cavernosum (d'Emmanuele di Villa Bianca et al, 2005). A functional magnetic resonance imaging placebo-controlled study provided an in vivo demonstration that apomorphine modulates cortical and subcortical brain structures in psychogenic ED patients, with a downregulation of frontal limbic areas showing increased activity (Montorsi et al, 2003a). As shown in animals,

an additional action at the level of the spinal cord has also been reported in humans [START_REF] Pehek | The effects of intrathecal administration of the dopamine agonist apomorphine on penile reflexes and copulation in the male rat[END_REF][START_REF] Giuliano | Apomorphine SL (Uprima): preclinical and clinical experiences learned from the first central nervous system-acting ED drug[END_REF]. In the beginning of the 2000's, Ixense® (Takeda, 2001) and Uprima® (Abbott Laboratories, 2001) were commercialized for impotence/erectile dysfunction as the first treatment for ED with a central mode of action (sublingual apomorphine 2 and 3 mg). Erection usually occurred within 20 min [START_REF] Altwein | Oral treatment of erectile dysfunction with apomorphine SL[END_REF] with an overall good tolerability. Adverse events were usually mild to moderate: headache, nausea/vomiting, dizziness, yawning, hypotension/vasovagal-type symptoms, chest pain, mouth ulceration, taste perversion or stomatitis (the latter being due to the sublingual administration) [START_REF] Altwein | Oral treatment of erectile dysfunction with apomorphine SL[END_REF][START_REF] Giuliano | Apomorphine SL (Uprima): preclinical and clinical experiences learned from the first central nervous system-acting ED drug[END_REF]Montorsi, 2003b;[START_REF] Perimenis | Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study[END_REF][START_REF] Mohee | The evaluation of apomorphine for the treatment of erectile dysfunction[END_REF]. Hypersensitivity reactions (facial edema) or syncope occurred very rarely (MacLennan et al, 2004;[START_REF] Afif-Abdo | Comparative cross-over study of sildenafil and apomorphine for treating erectile dysfunction[END_REF][START_REF] Altwein | Oral treatment of erectile dysfunction with apomorphine SL[END_REF]. Despite a promising entry (fast absorption and rapid onset of action, favorable tolerability and safety profile especially in patients receiving nitrates - [START_REF] Montorsi | Apomorphine to Uprima: the development of a practical erectogenic drug: a personal perspective[END_REF][START_REF] Heaton | Characterising the benefit of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction[END_REF][START_REF] Perimenis | Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study[END_REF], Ixense® and Uprima® were soon to be discontinued (respectively in 2004 and 2006), facing the competition of the phosphodiesterase type 5 inhibitors (PDE5I) family [START_REF] Afif-Abdo | Comparative cross-over study of sildenafil and apomorphine for treating erectile dysfunction[END_REF]. Compared to sildenafil, apomorphine use was associated with lower efficacy, lower satisfaction rates, and troublesome adverse events [START_REF] Maclennan | Examination of the safety and use of apomorphine prescribed in general practice in England as a treatment for erectile dysfunction[END_REF][START_REF] Porst | Comparative trial of treatment satisfaction, efficacy and tolerability of sildenafil versus apomorphine in erectile dysfunction--an open, randomized cross-over study with flexible dosing[END_REF][START_REF] Albersen | The future is today: emerging drugs for the treatment of erectile dysfunction[END_REF]. A postmarketing surveillance study led in England, within an observational cohort of more than 10 000 patients from general medical practice, showed that 40% of the patients had stopped apomorphine at the end of the first month and more than 70% stopped using apomorphine after 6 months, the main reason being that it was "not effective" (MacLennan et al, 2004).

However, several points are to be considered. Firstly, as a central initiator, apomorphine is not an adequate option for arteriogenic ED [START_REF] Afif-Abdo | Comparative cross-over study of sildenafil and apomorphine for treating erectile dysfunction[END_REF]) because it requires erectile potential [START_REF] Heaton | Recovery of erectile function by the oral administration of apomorphine[END_REF]. It is, however, a good option in cases of non-arteriogenic ED, psychogenic ED, and contraindication to sildenafil [START_REF] Montorsi | Apomorphine to Uprima: the development of a practical erectogenic drug: a personal perspective[END_REF][START_REF] Perimenis | Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study[END_REF]. One can therefore wonder if the 10 000 patients of the Maclennan's study were correctly screened at first (distinction between types of ED and distinction between ED and problems with libido, orgasm or ejaculation) and/or if apomorphine was correctly used, the tablets being ineffective if swallowed (MacLennan et al, 2004). To be noted, a small study (N=22) on patients with chronic spinal cord injury and erectile dysfunction showed overall low rates of response (Strebel et al, 2003). Secondly, many studies were carried out with an open design and failed to take into account confounding factors like apomorphine dose and frequency of administration, patient age, ED etiology (arteriogenic vs non-arteriogenic), coexisting disease and/or concomitant treatments (MacLennan et al, 2004;[START_REF] Afif-Abdo | Comparative cross-over study of sildenafil and apomorphine for treating erectile dysfunction[END_REF]. Reasons making patients poor responders to apomorphine were also not investigated. Finally, the "on demand" scheme of administration (based on sildenafil), might not be the best for apomorphine. Sequential administration [START_REF] Heaton | Sequential administration enhances the effect of apomorphine SL in men with erectile dysfunction[END_REF] and a daily regimen [START_REF] Caruso | Efficacy and safety of daily intake of apomorphine SL in men affected by erectile dysfunction and mild hyperprolactinemia: a prospective, open-label, pilot study[END_REF] were indeed shown to be more effective than the "taken-as needed" scheme.

The multifactorial nature of ED requires a multidimensional approach (Costa et al, 2001;[START_REF] Heaton | Characterising the benefit of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction[END_REF].

A synergistic approach, combining centrally acting drugs with peripherally acting drugs like sildenafil [START_REF] Park | Potentiation of apomorphine effect on sildenafil-induced penile erection in conscious rabbits[END_REF]Huang et al, 2008;[START_REF] Solayman | PIH4 Is Sildenafil -Apomorphine Sublingual Combination Significantly More Effective than Sublingual Sildenafil in Treating Erectile Dysfunction?[END_REF] or other vasoactive drugs [START_REF] Lammers | Combination therapy for erectile dysfunction: a randomized, double blind, unblinded activecontrolled, cross-over study of the pharmacodynamics and safety of combined oral formulations of apomorphine hydrochloride, phentolamine mesylate and papaverine hydrochloride in men with moderate to severe erectile dysfunction[END_REF]) could be advised, and accompanied by psychosexual counselling (Costa et al, 2001). In conscious rabbits, apomorphine enhances the sildenafil-induced erection without causing an additional decrease in blood pressure [START_REF] Park | Potentiation of apomorphine effect on sildenafil-induced penile erection in conscious rabbits[END_REF]. This approach should be tested in human, with caution regarding potential additional hypotensive effect.

Furthermore, sublingual apomorphine could represent a good alternative pharmacotherapeutic option for impotent patients also suffering from neurodegenerative diseases, like PD, multiple sclerosis atrophy (MSA)

or even multiple sclerosis (MS) [START_REF] O'sullivan | Apomorphine-induced penile erections in Parkinson's disease[END_REF][START_REF] Dasgupta | Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies[END_REF][START_REF] Flabeau | Multiple system atrophy: current and future approaches to management[END_REF][START_REF] Bronner | Management of sexual dysfunction in Parkinson's disease[END_REF][START_REF] Perez-Lloret | Current Concepts in the Treatment of Multiple System Atrophy[END_REF]. Surprisingly (particularly for PD), its use in these indications has not been assessed yet, despite being advised by O'Sullivan & Hughes (1998).

When considering a customized approach [START_REF] Heaton | Characterising the benefit of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction[END_REF], apomorphine remains relevant in ED, particularly for a subset of patients [START_REF] Mohee | The evaluation of apomorphine for the treatment of erectile dysfunction[END_REF], where it can even represent a first-line oral therapy [START_REF] Heaton | Characterising the benefit of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction[END_REF]Montorsi, 2003b;[START_REF] Perimenis | Efficacy of apomorphine and sildenafil in men with nonarteriogenic erectile dysfunction. A comparative crossover study[END_REF][START_REF] Albersen | The future is today: emerging drugs for the treatment of erectile dysfunction[END_REF]. A new inhalation device administering lower doses of apomorphine (VR004) was developed at the end of the 2000's and seemed rather promising [START_REF] Riley | Inhalation device allows novel administration of apomorphine in men with erectile dysfunction-efficacy and safety findings[END_REF], but its development for male sexual dysfunction has been suspended, apparently due to lack of partners [START_REF] Albersen | The future is today: emerging drugs for the treatment of erectile dysfunction[END_REF]. Research efforts and clinical trials targeting subgroups of ED and neurodegenerative patients are therefore needed, as sexual disorders significantly contribute to lower the quality of life of both patients and spouses [START_REF] Porst | Comparative trial of treatment satisfaction, efficacy and tolerability of sildenafil versus apomorphine in erectile dysfunction--an open, randomized cross-over study with flexible dosing[END_REF].

Women

Following the discovery that apomorphine could modify the sexual response in male rats, experiments were conducted in female rats, demonstrating that dopamine is also involved in the regulation of female sexual behavior [START_REF] Hamburger-Bar | Apomorphine: facilitation of sexual behaviour in female rats[END_REF][START_REF] Foreman | Role of hypothalamic dopaminergic receptors in the control of lordosis behavior in the female rat[END_REF]. Evidence currently suggest that similar neural substrates (hypothalamic areas) and pathways mediate the female and male sexual behaviors [START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF]. Female sexual response depends on hormonal factors (that vary throughout the reproductive cycle) and is characterized by hemodynamic changes (clitoral engorgement and vaginal vasocongestion) involving NO, sympathetic, parasympathetic and noradrenergic pathways [START_REF] Beharry | Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response[END_REF][START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF].

Apomorphine (acute SC injection, 0.25mg/kg) increases sexual behavior (lordosis response) in oestrogen and oestrogen+progesterone-primed spayed female rats, this facilitatory effect lasting up to 48h after administration [START_REF] Hamburger-Bar | Apomorphine: facilitation of sexual behaviour in female rats[END_REF][START_REF] Foreman | Role of hypothalamic dopaminergic receptors in the control of lordosis behavior in the female rat[END_REF]. In anesthetized rabbits, apomorphine (0.1 and 0.2mg/kg, IV) increases nerve-stimulated (but not basal) clitoral intracavernosal and vaginal wall arterial inflow, hence increasing engorgement [START_REF] Tarcan | Systemic administration of apomorphine improves the hemodynamic mechanism of clitoral and vaginal engorgement in the rabbit[END_REF]. These effects are accompanied with a significant decrease in diastolic arterial pressure [START_REF] Tarcan | Systemic administration of apomorphine improves the hemodynamic mechanism of clitoral and vaginal engorgement in the rabbit[END_REF]. Greater concentrations are less effective and produce adverse effects [START_REF] Tarcan | Systemic administration of apomorphine improves the hemodynamic mechanism of clitoral and vaginal engorgement in the rabbit[END_REF]. In ovariectomized Long-Evans female rats, the administration of low doses of apomorphine (80 µg/kg, SC) to the medial preoptic areas induces a significant increase in appetitive sexual behaviors (solicitations, hops and/or darts) [START_REF] Graham | Infusion of the dopamine agonist apomorphine to the medial preoptic are facilitates appetitive sexual behaviours of female rats[END_REF]. Another experiment on female Wistar rats showed that the magnitude of apomorphine-induced sexual changes (genital grooming, genital engorgement) depends on the stage of the estrous cycle [START_REF] Beharry | Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response[END_REF]. Taken together, these preclinical data (patterned behavioral sexual response and genital changes) suggest that apomorphine may play a role in female sexual disorders, through a modulation of hemodynamic mechanism and dopaminergic pathways, in a rapid and transient way.

Contrary to erectile dysfunction, apomorphine effect has been poorly explored in female sexual dysfunction (FSD) [START_REF] Beharry | Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response[END_REF][START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF]. They are four types of FSD: sexual pain disorder (dyspareunia, vaginismus), hypoactive sexual desire disorder (lack of mental excitement and physical genital congestion), sexual arousal disorder and orgasmic disorder [START_REF] Beharry | Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response[END_REF]Buster, 2013). The pathophysiology remains unclear but is probably multifactorial, with a combination of organic (vascular, neurological, hormonal) and underlying psychological disorders [START_REF] Beharry | Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response[END_REF][START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF][START_REF] Caruso | Placebo-controlled study on efficacy and safety of daily apomorphine SL intake in premenopausal women affected by hypoactive sexual desire disorder and sexual arousal disorder[END_REF]. Highly prevalent, FSD affects at least a third of women, with various degrees of severity [START_REF] Beharry | Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response[END_REF][START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF], impairing life quality and interpersonal relationships [START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF]. In a prospective, doubleblind and randomized cross-over study on women with orgasmic sexual dysfunction (N=24, age 32 ± 9.69 years), a single administration of sublingual apomorphine (3mg) was shown to induce both objective (clitoral hemodynamic changes) and subjective (arousal and lubrication) changes in the sexual arousal phase, compared to placebo [START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF]. By contrast, differences between placebo and apomorphine on orgasm were not statistically significant, but confounding factors due to a research situation might be an explanation [START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF]. In another study, apomorphine (2-3mg sublingually) efficacy was assessed in premenopausal women (N=62, 26-45 years old) affected by sexual arousal disorder, either in an "as required" or daily use regimen [START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF]. The daily regimen was more effective than the "taken-as needed" [START_REF] Caruso | Placebo-controlled study on efficacy and safety of daily apomorphine SL intake in premenopausal women affected by hypoactive sexual desire disorder and sexual arousal disorder[END_REF] in increasing sexual desire, orgasm, enjoyment and satisfaction [START_REF] Caruso | Placebo-controlled study on efficacy and safety of daily apomorphine SL intake in premenopausal women affected by hypoactive sexual desire disorder and sexual arousal disorder[END_REF], which echoes previously mentioned results from ED studies [START_REF] Caruso | Efficacy and safety of daily intake of apomorphine SL in men affected by erectile dysfunction and mild hyperprolactinemia: a prospective, open-label, pilot study[END_REF]. Reported adverse events during apomorphine treatment were usually mild to moderate (nausea, vomiting, dizziness and headache) and affected a small proportion of the studied population [START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF][START_REF] Bechara | A double blind randomized placebo control study comparing the objective and subjective changes in female sexual response using sublingual apomorphine[END_REF]. To be noted, the MacLennan's study cohort showed that apomorphine SL (2-3mg) was prescribed to 8 women (median age 50 years old) for decreased libido, pain and/or sexual arousal phase dysfunction (Maclennan et al, 2004). Unfortunately, no detailed data regarding patients' profile, adverse events or apomorphine efficacy are available. It would be interesting to lead a retrospective study (2001)(2002)(2003)(2004)(2005)(2006) and to collect clinical data from these uncommon prescriptions of Uprima® and Ixense® in the countries where they were available.

Although data are scarce, they do suggest that apomorphine may improve some aspects of FSD. Future work is needed in this niche area, with longitudinal prospective study exploring the efficacy of apomorphine in premenopausal and postmenopausal women, as well as in types of FSD other than sexual arousal disorders and orgasmic disorders.

Apomorphine and Neuroleptic (-Like) Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare, acute, severe and potentially lethal idiosyncrasic reaction to antipsychotics, mainly neuroleptics [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF]. It is usually characterized by rigidity, hyperthermia, altered mental status and autonomic dysfunction, typically associated with elevated serum creatinine phosphokinase levels and white blood cell count [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF][START_REF] Oruch | Neuroleptic malignant syndrome: an easily overlooked neurologic emergency[END_REF]. The malignant syndrome in PD or "neuroleptic-like malignant syndrome" (NLMS) is quite similar to NMS: potentially fatal, with fever, altered levels of consciousness, muscle tone increase, autonomic disturbance and elevated serum creatine kinase levels [START_REF] Ikebe | Prevention and treatment of malignant syndrome in Parkinson's disease: a consensus statement of the malignant syndrome research group[END_REF]. It is usually caused by an abrupt-reduction or cessation in antiparkinsonian drugs (levodopa or dopaminergic agonists), but it can also be precipitated by intercurrent infections, hot weather or dehydration [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Ikebe | Prevention and treatment of malignant syndrome in Parkinson's disease: a consensus statement of the malignant syndrome research group[END_REF][START_REF] Douglas | It was not just a heatwave! Neuroleptic malignant-like syndrome in a patient with Parkinson's disease[END_REF][START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF].

The pathophysiology of NMS and NLMS remains unclear. In NMS, the commonly accepted model is an abrupt blockade of dopamine receptors, particularly in the nigrostriatal and hypothalamic pathways [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF]. In NLMS, postulated pathophysiologic mechanisms include central dopamine receptor dysregulation, autonomic dysfunction and skeletal muscle hypermetabolism (Bonnuccelli et al, 1991;[START_REF] Douglas | It was not just a heatwave! Neuroleptic malignant-like syndrome in a patient with Parkinson's disease[END_REF]. In both cases, specific treatment remain controversial, but mostly relies on supportive treatments (e.g. antipyretics, intravenous fluids) and dopaminergic agonists, with variable results (Bonnuccelli et al, 1991;[START_REF] Colosimo | Clinical usefulness of apomorphine in movement disorders[END_REF][START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Ikebe | Prevention and treatment of malignant syndrome in Parkinson's disease: a consensus statement of the malignant syndrome research group[END_REF][START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF].

Apomorphine, with its SC administration, rapid absorption into the brain and pleiotropic pharmacological profile, appears to be a good candidate for both NMS and NLMS [START_REF] Colosimo | Clinical usefulness of apomorphine in movement disorders[END_REF][START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF].

A few successfully treated cases of NMS [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Lattanzi | Subcutaneous apomorphine for neuroleptic malignant syndrome[END_REF] and NLMS (Bonnuccelli et al, 1991;[START_REF] Cunningham | Controlled-release delivery of L-dopa associated with nonfatal hyperthermia, rigidity, and autonomic dysfunction[END_REF][START_REF] Douglas | It was not just a heatwave! Neuroleptic malignant-like syndrome in a patient with Parkinson's disease[END_REF], summarized in Table 4, support these assumptions.

Briefly, in NMS, the initiation of apomorphine monotherapy (2mg every 3 to 4 h) was rapidly followed (<48h) by clinical improvement, with a decrease in muscle tone, fever and frequency of contractions [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Lattanzi | Subcutaneous apomorphine for neuroleptic malignant syndrome[END_REF][START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF]. In two cases, apomorphine monotherapy successfully resolved the NMS within 4 days [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Lattanzi | Subcutaneous apomorphine for neuroleptic malignant syndrome[END_REF]. In another case, the patient died despite partial remission of extrapyramidal signs [START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF]. The delayed diagnosis might have prevented a favorable outcome in an already weakened patient [START_REF] Gambassi | Fatal neuroleptic malignant syndrome in a previously long-term user of clozapine following its reintroduction in combination with paroxetine[END_REF], as prompt treatment is mandatory [START_REF] Oruch | Neuroleptic malignant syndrome: an easily overlooked neurologic emergency[END_REF]. To be noted, the total daily dose of apomorphine was also lower (12 vs 16mg /day) in the latter case. The few reported cases of NMLS in PD (N=4) show that apomorphine, associated with L-dopa or other dopaminergic agonists, led to a quick resolution of the various symptoms (Bonnuccelli et al, 1991;[START_REF] Cunningham | Controlled-release delivery of L-dopa associated with nonfatal hyperthermia, rigidity, and autonomic dysfunction[END_REF][START_REF] Douglas | It was not just a heatwave! Neuroleptic malignant-like syndrome in a patient with Parkinson's disease[END_REF]. Though not supported yet by major evidence [START_REF] Oruch | Neuroleptic malignant syndrome: an easily overlooked neurologic emergency[END_REF], SC apomorphine deserves to be considered as a good and practical alternative for NMS and NMLS, particularly when oral route is hindered [START_REF] Wang | Treatment of neuroleptic malignant syndrome with subcutaneous apomorphine monotherapy[END_REF][START_REF] Lattanzi | Subcutaneous apomorphine for neuroleptic malignant syndrome[END_REF][START_REF] Douglas | It was not just a heatwave! Neuroleptic malignant-like syndrome in a patient with Parkinson's disease[END_REF].

Apomorphine and cancer

Several preclinical studies have demonstrated that apomorphine is a potential anticancer agent, with a wide spectrum of activity (see Table 1). As dopaminergic agonists are known to produce an antiproliferative effect on different cell lines [START_REF] Schrell | Growth of cultured human cerebral meningiomas is inhibited by dopaminergic agents. Presence of high affinity dopamine-D1 receptors[END_REF][START_REF] Drewett | Apoptosis in the anterior pituitary gland of the rat: studies with estrogen and bromocriptine[END_REF]Chiarenza et al, 2003), and dopamine to play a role in several types of cancer [START_REF] Jung | Apomorphine suppresses TNF-α-induced MMP-9 expression and cell invasion through inhibition of ERK/AP-1 signaling pathway in MCF-7 cells[END_REF], the endocrine response to apomorphine (0.01 mg/kg/body weight) was assessed in cancer patients [START_REF] Lissoni | Psychooncology and cancer progression-related alterations of pleasure-associated neurochemical system: Abnormal neuroendocrine response to apomorphine in advanced cancer patients[END_REF]. Compared to the control group ( 6males), GH and cortisol mean were significantly higher after apomorphine in the metastatic cancer patients (metastatic solid neoplasms, 10 males), suggesting an association between cancer progression and an altered dopaminergic sensitivity [START_REF] Lissoni | Psychooncology and cancer progression-related alterations of pleasure-associated neurochemical system: Abnormal neuroendocrine response to apomorphine in advanced cancer patients[END_REF]. In vitro experiments have shown that R-(-) and S-(+)apomorphine have a potent antiproliferative effect on various animal and human cancer cell lines (Table 1), and are able to suppress metastatic progression [START_REF] Kondo | Suppression of tumor cell growth and mitogen response by aporphine alkaloids, dicentrine, glaucine, corydine, and apomorphine[END_REF][START_REF] Seko | Apomorphine inhibits the growth-stimulating effect of retinal pigment epithelium on scleral cells in vitro[END_REF][START_REF] Scarselli | Apomorphine has a potent antiproliferative effect on Chinese hamster ovary cells[END_REF][START_REF] Maggio | Dopamine agonists and analogues have an antiproliferative effect on CHO-K1 cells[END_REF][START_REF] Chiarenza | Apomorphine, dopamine and phenylethylamine reduce the proportion of phosphorylated insulin receptor substrate 1[END_REF][START_REF] Pardini | Dose-dependent induction of apoptosis by R-apomorphine in CHO-K1 cell line in culture[END_REF][START_REF] Meredith | Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma[END_REF][START_REF] Jung | Apomorphine suppresses TNF-α-induced MMP-9 expression and cell invasion through inhibition of ERK/AP-1 signaling pathway in MCF-7 cells[END_REF]. Antiproliferative mechanisms involve oxidative stress (catechol moiety, [START_REF] Pardini | Dose-dependent induction of apoptosis by R-apomorphine in CHO-K1 cell line in culture[END_REF], apoptotic cell death [START_REF] Pardini | Dose-dependent induction of apoptosis by R-apomorphine in CHO-K1 cell line in culture[END_REF][START_REF] Meredith | Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma[END_REF], mitochondrial regulation [START_REF] Lee | Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures[END_REF], as well as inhibition of several signaling pathways (glutaminase enzyme [START_REF] Thomas | Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors[END_REF]ERK Jung & Lee, 2017;interleukin IL-2 Kondo et al, 1990, protein kinase PKC/PKA Wang et al, 1997;[START_REF] Scarselli | Apomorphine has a potent antiproliferative effect on Chinese hamster ovary cells[END_REF]MDM2-p53 interaction Ishiba et al, 2017).

These preliminary data are very encouraging, but whether they can be reproduced in vivo and harnessed to formulate a deliverable therapeutic remains uncertain [START_REF] Meredith | Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma[END_REF]. However, a very recent in vivo study has shown that treatment with apomorphine (5 mg/kg, 3 times weekly for 1 month, a treatment protocol derived from previous AD model), prevented (human lung-derived) brain metastases formation in a NOD-SCID mice brain metastasis initiating cell model [START_REF] Singh | Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis[END_REF]. Apomorphine induced an inhibition of micrometastatic growth as well as subsequent macrometastases, possibly through a targeting of premetastasisassociated genes (KIF16B, SEPW1, and TESK2) ; these results support further use of apomorphine in cancer therapy, particularly as a way to prevent metastases initiation [START_REF] Singh | Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis[END_REF]. Studies exploring the possible anti-invasive effects of apomorphine on different types of cancer are currently underway [START_REF] Jung | Apomorphine suppresses TNF-α-induced MMP-9 expression and cell invasion through inhibition of ERK/AP-1 signaling pathway in MCF-7 cells[END_REF].

Further work is needed to assert which types and forms of cancer are more likely to be targeted by apomorphine (potential candidates: glioma, glioblastoma, melanoma, meningioma, [START_REF] Lee | Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures[END_REF][START_REF] Singh | Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis[END_REF], and precisely determine the mechanism(s) involved (regulatory effects on tumor progression and/or metastasis).

Conclusion & perspectives

Fewer risks, lower costs and shorter timelines [START_REF] Breckenridge | Overcoming the legal and regulatory barriers to drug repurposing[END_REF] have prompted a renewed interest for repurposing old drugs. Apomorphine, a 150-year old pluripotent agent, seems to be an ideal candidate for repurposing. Historically, its use has certainly not been limited to PD, and even if some of these former indications have been consigned to history books, new prospects are emerging. This review fostered several repurposing opportunities for apomorphine. However, data are still scarce, and the fact that apomorphine may bring significant benefit in comparison with existing therapies in the previously mentioned indications has yet to be confirmed with larger, prospective randomized and placebo controlled studies. In addition, several pitfalls have to be overcome [START_REF] Breckenridge | Overcoming the legal and regulatory barriers to drug repurposing[END_REF]) before a generalization of apomorphine use: legal, regulatory (phase II and III studies) and economic barriers (apomorphine being a mature drug), selecting the appropriate dose for each indication and patient, as well as offering new ways of administration and delivery systems. Another approach would be to synthetize apomorphine derivatives to overcome its inherent instability and short half-life, or to enhance targeting, with lipid-drug conjugates [START_REF] Irby | Lipid-Drug Conjugate for Enhancing Drug Delivery[END_REF] or nanostructured lipid carriers [START_REF] Hsu | Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug[END_REF]. Despite these limitations, there is now sufficient experimental evidence to support a rapid and efficient repurposing of apomorphine.  Pr Marc Vérin served on scientific advisory boards for Orkyn and Aguettant and received speech honorarium from Orkyn, Aguettant, Medtronic and Teva.

  Repurposing opportunities for apomorphine: summary of the possible indications and associated mechanisms. AD: Alzheimer's disease; ERK: extracellular signal-regulated kinases; IRS-1: insulin receptor substrate 1; NDEA: N-nitrosodiethylamine; Nrf2-ARE: NF-E2-related factor 2antioxidant responsive element; PKC/A: phosphokinase C/A; PLMS: periodic limb movements during sleep; ROS: reactive oxygen species inhibition (neoplasia and In vitro: Kondo et al, None at the time of excitotoxicity

  Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor disturbance (both hyperkinetic and hypokinetic), cognitive impairment and a wide variety of neuropsychiatric symptoms, including psychosis, anxiety and depression[START_REF] Mccolgan | Huntington's disease: a clinical review[END_REF]. The autosomal dominantly inherited mutation on the huntingtin gene induces the production of a mutant huntingtin (mHTT) that triggers neuronal dysfunction and death (particularly of medium-sized spiny neurons), through protein aggregation, synaptic dysfunction, mitochondrial toxicity and decreased rate of axonal transport[START_REF] Mccolgan | Huntington's disease: a clinical review[END_REF].



  Reduction of AIM scores by 40 to 55% at the doses of 1-2mg and by 75-85% at the doses of 3-4mg Reduction of both amplitude and frequency of the choreic movements in a dose-related way. Beneficial effect within few minutes, lasting about 60 min (peak effect: 24-40min)

  improvement of awareness levels) and clinical recovery (recovery of consciousness) involve the functional restoration of disrupted networks[START_REF] Chen | Impact of Traumatic Brain Injury on Dopaminergic Transmission[END_REF][START_REF] Pistoia | Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?[END_REF]. Dopaminergic-targeted strategies are common in rehabilitative programs[START_REF] Chen | Impact of Traumatic Brain Injury on Dopaminergic Transmission[END_REF] and several studies have sporadically shown that levodopa, pramipexole, bromocriptine or amantadine can help regain consciousness and accelerate recovery, particularly for patients showing signs of parkinsonism[START_REF] Pistoia | Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?[END_REF][START_REF] Fridman | Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury[END_REF]. Being a direct nonspecific dopaminergic agonist with potential neurorecovery properties and parenteral administration, apomorphine appears theoretically of great interest in DOC. To date, only eight cases (4 males, aged 22-41 years) of functional recovery from VS (N=6) or MCS (N=2) with apomorphine have been documented, in an

Table 4 :

 4 Summary of the case reports of NMS and NLMS treated with apomorphine. APO: apomorphine; ATB: antibiotics: IV: intravenous; NLMS: neuroleptic-like malignant syndrome; NMS: NLMS: neuroleptic malignant syndrome; PD : Parkinson's disease ; SC : subcutaneous;



  Dr Manon Auffret: none  Dr Sophie Drapier served on scientific advisory boards for Orkyn and Aguettant, received speech honorarium from Orkyn, Aguettant, Medtronic, Teva and received PHRC grants from the French Ministry of Health.

Table 2 :

 2 Summary of the results of the clinical trials on apomorphine use in Huntington's disease.

AIM: abnormal involuntary movements; AIMS: Abnormal Involuntary Movement Scale; F: female; GH: growth hormone; M: male; N/A: not available; TID: three times a day; UHDRS: Unified Huntington's Disease Rating Scale

Table 3 :

 3 Results from Fridman's studies, exploring the efficacy of apomorphine in vegetative and minimally conscious states patients due to sever traumatic brain injury[START_REF] Fridman | Fast awakening from minimally conscious state with apomorphine[END_REF][START_REF] Fridman | Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury[END_REF]. APO: apomorphine;

	CNCS: Coma Near-Coma Scale; DRS: Disability Rating Scale; F: female; M: male; MCS: minimally conscious
	state; TBI: traumatic brain injury; VS: vegetative state
	Diagnosis Patient	Drugs used prior to	Apomorphine treatment	CNCS		DRS
		(age, sex,	apomorphine	(initially planned for 84	(0-44)		(0-29)
		location)		days)	Baseline 1	Baseline 1
						year		year
	MCS	25/M	Methylphenidate (15mg x	Up to 8 mg/h	20	0	21	6.5
		Argentina	12 days), Bromocriptine	Initiated 104 days after TBI
			(10mg x 8 days)	Improvement within 24 h
				Treatment duration: 180
				days
		22/F	Levodopa/carbidopa	Up to 4 mg/h	26	0	21	6
		Israël	(250/25mg x 35 days)	Initiated 60 days after TBI
	VS	30/F	N/A	Up to 8	33	0	22	9.5
		Argentina		mg/h
				Initiated 46 days after TBI
		18/M	Levodopa/carbidopa	Up to 4 mg/h	41	0	27	3
		Israël	(250/25mg x1.5x 11days)	Initiated 57 days after TBI
		18/F	Amantadine (200mg twice a	Up to 6 mg/h	38	0	26	10.5
		Israël	day), Levodopa/carbidopa	Initiated 62 days after TBI
			(250/25mg)	Treatment duration: 75 days
		22/M	Levodopa/carbidopa	Up to 6 mg/h	36	0	24	13
		Israël	(250/25 mgx11 days,	Initiated 68 days after TBI
			250/25mgx1.5x4 days)	&
				discontinued at day 56.
				Patient still in MCS,
				subsequently responded
				after reinstatement of
				levodopa/carbidopa at day

Funding source & Conflict of interest: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare that there are no conflicts of interest relevant to this work.

Conflicts of interest:

No targeted funding reported.