WO2012171653A1

WO2012171653A1 - Sarizotan for use in the treatment of attention deficit hyperactivity disorder (adhd)

Info

Publication number: WO2012171653A1
Application number: PCT/EP2012/002538
Authority: WO
Inventors: Barbara Valastro
Original assignee: Merz Pharma Gmbh & Co. Kgaa
Priority date: 2011-06-15
Filing date: 2012-06-15
Publication date: 2012-12-20

Abstract

The present invention relates to the efficient treatment of an individual afflicted with attention deficit hyperactivity disorder (ADHD), the instant treatment comprising administering to the individual an effective amount of sarizotan or a pharmaceutically acceptable salt thereof.

Description

SARIZOTAN FOR USE IN THE TREATMENT OF

ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)

FIELD OF THE INVENTION

[0001] The present invention relates to the efficient treatment of an individual afflicted with attention deficit hyperactivity disorder (ADHD), the instant treatment comprising administering to the individual an effective amount of sarizotan or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

[0002] This invention relates to an innovative method of treating patients afflicted with attention deficit hyperactivity disorder (ADHD).

[0003] ADHD is a heritable disease characterized by inattention, impulsivity and hyperactivity. Although it was earlier defined as a pediatric indication, it is recognized since 1990 that ADHD is not exclusively a childhood disorder but rather a chronic disorder, which persists into adulthood (Lange et al., Atten. Defic. Hyperact. Disord. 2010; 2; 241-55). From a pathophysiological point of view, neuroimaging studies have demonstrated abnormalities in the frontal-subcortical-cerebellar system, which are areas associated with regulation of attention and motor behavior. However, no unique genetic, biological or neurological pathology has been identified so far for ADHD (for a review of pharmacogenetic efforts for the identification of genetic factors involved in development and treatment of ADHD see: Froehlich et al., CNS Drugs 2010, 24, 99-1 17). It has been observed, however, that dopamine (DA) transporters are increased in ADHD patients (Dougherty et al., Lancet 1999, 354, 2132-2133; Krause et al., Neurosci. Lett. 2000, 285, 107-1 10), and it has been hypothesized that a deficit of DA in certain areas of the brain is responsible for at least certain aspects of the disease.

[0004] Thus, current treatment options are mainly directed at increasing DA levels. Methylphenidate (MPH) and amphetamine (AMPH) are two stimulant medications commonly used for the treatment of ADHD. Based on the literature, MPH improves the problems in 60-70% of young and adult ADHD patients, while this number can rise up to 80% for patients treated with amphetamine (Oades, Progress in Brain Research, 172 (2008) 543-565). However, the efficacy of both substances is less certain when used for a period longer than 3-5 years (for a review of recent developments in the treatment of ADHD see: May and Kratochvil, Drugs 2010, 70, 15-40).

[0005] Although the mode of action of MPH is still not completely understood, it is believed to act as dopamine (DA) and noradrenalin transporter blocker, which results in an increase of extracellular DA in the synaptic cleft. This effect has been observed in rodents and in humans treated orally with therapeutic doses of MPH (Volkow et al., J. Neurosci. 2001 , 21 , RC121). It has furthermore been shown that MPH affects vesicular monoamine transporter-2 (VMAT-2) in membrane-associated vesicle and cytoplasmic vesicle subcellular fractions, so that MPH influences trafficking, DA sequestration function, DA content, and exocytotic DA release function of synaptic vesicles (Volz et al., J. Pharmacol. Exp. Ther. 2007, 323, 738-45; Volz et al., J. Pharmacol. Exp. Ther. 2008, 327, 161-7; Volz et al., Ann. N. Y. Acad. Sci. 2008, 1139, 285-90).

[0006] AMPH on the other side increases the release of DA in the synaptic cleft, thereby increasing the amount of DA available to interact with the different DA receptor subtypes located in the synapse. In one theory, AMPH is supposed to interact with intracellular vesicles so that DA is released from the vesicles to the cytosol, followed by a reverse transport of DA through DA transporters (DATs) to the extracellular space. According to another theory, AMPH directly interacts with DATs, causing both the reverse transport and a DA efflux from the intra- to the extracellular space (Kahlig et al., Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 3495-500).

[0007] It has been suggested by Fan et al. (Fan et al., Neurobiol. Dis. 2010, 37, 228- 236) that D2 agonists should be useful in ADHD based on data obtained in a Coloboma mouse model of ADHD. However, this paper added little clarity to the field as D2 antagonists not only reversed the positive effects of amphetamine in this model, but were also effective anti-ADHD agents in their own right. Furthermore, this paper casts doubts on any roles for D3 / D4 in ADHD despite the genetic link for D4. As such, it added little clarity to the field but rather raised contradictions in our understanding of the modes of action involved.

[0008] In addition, D4 receptors are associated with an increased risk for ADHD (Froehlich et al., loc. cit.) and D4 antagonists have been shown to reduce locomotor activity in the neonatal 6-OHDA model, a model of ADHD, where the level of hyperactivity correlates with increases in D4, but not D2 receptor expression (Zhang et al., Neuropsychopharmacology 2001 , 25, 624-32; Zhang et al., Psychopharmacology 2002, 161 , 100-106).

[0009] The serotonin receptor 5-HT7 was also suggested to be genetically linked to impulsive behaviour (Goldman et al., Ciba Found Symp. 1996, 194, 139-152) and it has been shown that antagonists of the receptor enhances impulsivity in naive adult rats (Leo et al., Genes, Brain and Behavior 2009, 8, 356-368) suggesting a beneficial effect of 5-HT7 agonists for the treatment of ADHD.

[0010] Thus, at present it is not yet finally resolved, which impact dopamine receptors and their agonists and/or antagonists may have on DA levels and their influence in ADHD.

[0011] Noteworthy, MPH- and AMPH-treated patients have to be closely monitored as a consequence of the compounds' abuse potential (see, for example, Summary of Product Characteristics (SmPC) for Ritalin^®). In contrast, Strattera^® (atomoxetine), which is used as a non-stimulant treatment for ADHD, has significantly less abuse liability than methylphenidate (Jasinski et al., Drug Alcohol Depend. 95 (2008) 140-6). However, head-to-head trials have demonstrated the drug to be less efficacious than stimulant drugs like AMPH or MPH (Kemner et al., Advances in Therapy 22 (2005) 498-512).

[0012] Therefore, there is still a medical need for a highly effective non-stimulating compound hence not leading to addiction. [0013] As described above, the therapeutic effect of MPH and AMPH is resulting from a direct impact on the dopaminergic transmission. However, it is well known that dopamine release is also controlled by the serotonin system, more specifically via modulation of the three major dopaminergic pathways, namely the nigrostriatal, mesolimbic, mesocortical pathway. Many preclinical studies have demonstrated that systemic administration of 5-HT1a receptor agonist increases DA release in the prefrontal cortex, a structure involved in selective attention and working memory (Alex and Pehek, Pharmacol. Ther. 2007, 113, 296-320). From a clinical point of view, two open trials and a double-blinded randomized clinical trial with the partial 5- HT1a agonist buspirone reported significant effects on ADHD (Malhotra and Santosh, J Am Acad. Child Adolesc. Psychiatry 1998, 37, 364-71 ; Niederhofer, Hum. Psychopharmacol. 2003, 18, 489-92; Davari-Ashtiani et al., Child Psychiatry Hum Dev. 2010, 41 , 641-8).

[0014] However, despite that fact that many attempts have been made to develop serotonergic agents for the treatment of ADHD, so far these attempts have had limited success in patients.

[0015] Thus, there is still a large unmet need to identify alternative medicaments for the treatment of ADHD.

[0016] The solution provided by the present invention to solve this problem, i.e. the use of a particular compound addressing both the serotonergic and the dopaminergic system, has so far not been achieved or suggested by the prior art.

SUMMARY OF THE INVENTION

[0017] The present invention relates to a method of treating ADHD in a subject in need thereof, comprising the step of administering an effective amount of sarizotan or a pharmaceutically acceptable salt thereof.

[0018] In certain embodiments of the method of the present invention, sarizotan is present as sarizotan hydrochloride. [0019] In certain embodiments of the method of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is administered in a range from about 1 mg to about 50 mg/day.

[0020] In certain other embodiments of the method of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is administered in an amount of up to about 3 mg/day.

[0021] In a further embodiment of the method of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is administered in a range from about 0.1 mg to about 3 mg/day.

[0022] In a still further embodiment sarizotan or a pharmaceutically acceptable salt thereof is administered in a range from about 0.5 mg to about 2.5 mg/day.

[0023] In a still further embodiment sarizotan or a pharmaceutically acceptable salt thereof is administered in a range from about 0.75 mg to about 2 mg/day.

[0024] In a still further embodiment sarizotan or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg/day.

[0025] In certain embodiments, the dosages mentioned in sections [0019] to [0024] are for administration to patients having a body weight of about 30 kg or more, and/or for patients with an age > 14 years, and are adjusted for patients with a body weight of less than 30 kg, and/or an age of 14 or less. Particularly, the dosage may be adjusted by administering between about half and about three quarters of the amount for a patient > 30 kg (alternatively: > 14 years). For example, a daily dosage of 1 mg for patients > 30 kg (alternatively: > 14 years) may be adjusted to a maximum of between about 0.5 mg and 0.75 mg per day for patients < 30 kg (alternatively: 14 years or less).

[0026] Alternatively, sarizotan may be administered on the basis of the body weight (mg/kg/day). In a particular embodiment, sarizotan or a pharmaceutically acceptable salt thereof is administered in a range from about 0.01 mg to about 0.03 mg/kg/day. [0027] In yet another embodiment of the method of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is administered once a day, particularly about 1 mg once a day for patients > 30 kg (alternatively: > 14 years), and about 0.5 mg once a day for patients < 30 kg (alternatively: 14 years or less).

[0028] In yet another embodiment of the method of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is administered in a multiple dose, for example twice a day (b.i.d.), or three times a day, particularly twice a day, particularly about 0.5 mg twice a day for patients > 30 kg (alternatively: > 14 years), and about 0.25 mg twice a day for patients < 30 kg (alternatively: 14 years or less).

[0029] In yet another embodiment of the method of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is administered in an oral formulation.

[0030] In yet another embodiment of the method of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is administered to the subject within up to 5 hours prior to an activity requiring an increased amount of attention, and/or a reduced amount of impulsivity and/or hyperactivity.

[0031] In yet another embodiment of the method of the present invention, the subject is undergoing treatment with a second pharmaceutical agent for the treatment of ADHD.

[0032] In yet another embodiment of the method of the present invention, the method further comprises administering at least one additional pharmaceutical agent, which has been shown to be effective for the treatment of ADHD.

[0033] In certain such embodiments, said second pharmaceutical agent is selected from (i) a stimulant medication, particularly selected from the list of methylphenidate (MPH) and amphetamine (AMPH), and (ii) a non-stimulant medication, particularly selected from the list of atomoxetine, a tricyclic antidepressant, and bupropion. [0034] In certain such embodiments, the second pharmaceutical agent is comprised in one of the pharmaceutical compositions listed in Section [0073] or [0074].

[0035] In another aspect, the present invention relates to a pharmaceutical composition comprising sarizotan or a pharmaceutically acceptable salt thereof for use in the treatment of ADHD.

[0036] In certain embodiments of the pharmaceutical composition of the present invention, sarizotan is present as sarizotan hydrochloride.

[0037] In certain embodiments of the pharmaceutical composition of the present invention, treatment of ADHD comprises administering sarizotan or a pharmaceutically acceptable salt thereof in an amount of up to 3 mg/day.

[0038] In a further embodiment of the pharmaceutical composition of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is for administration in a range from about 0.1 mg to about 3 mg/day.

[0039] In a still further embodiment sarizotan or a pharmaceutically acceptable salt thereof is for administration in a range from about 0.5 mg to about 2.5 mg/day.

[0040] In a still further embodiment sarizotan or a pharmaceutically acceptable salt thereof is for administration in a range from about 0.75 mg to about 2 mg/day.

[0041] In a still further embodiment sarizotan or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg/day.

[0042] In yet another embodiment of the pharmaceutical composition of the present invention, sarizotan or a pharmaceutically acceptable salt thereof (e.g., sarizotan hydrochloride) is for administration once a day, particularly about 1 mg once a day for patients > 30 kg, and about 0.5 mg for patients < 30 kg. twice a day (b.i.d.), particularly about 0.5 mg twice a day for patients > 30 kg, and about 0.25 mg/kg/d twice a day for patients < 30 kg, or three times a day, particularly once or twice a day. [0043] In yet another embodiment of the pharmaceutical composition of the present invention, sarizotan or a pharmaceutically acceptable salt thereof for administration in an oral formulation.

[0044] In yet another embodiment of the pharmaceutical composition of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is for administration to the subject within up to 5 hours prior to an activity requiring an increased amount of attention, and/or a reduced amount of impulsivity and/or hyperactivity.

[0045] In yet another embodiment of the pharmaceutical composition of the present invention, the subject is undergoing treatment with at least one additional pharmaceutical agent for the treatment of ADHD.

[0046] In yet another embodiment of the pharmaceutical composition of the present invention, sarizotan or a pharmaceutically acceptable salt thereof is for administration in combination with at least one additional pharmaceutical agent, which has been shown to be effective for the treatment of ADHD.

[0047] In certain such embodiments, said at least one additional pharmaceutical agent is selected from (i) a stimulant medication, particularly selected from the list of methylphenidate (MPH) and amphetamine (AMPH), and (ii) a non-stimulant medication, particularly selected from the list of atomoxetine, a tricyclic antidepressant, and bupropion.

[0048] In certain such embodiments, the at least one additional pharmaceutical agent is comprised in one of the pharmaceutical compositions listed in Section [0073] or [0074].

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 shows the T-maze apparatus used in Example 1 for determining the effect of sarizotan on impulsivity in juvenile rats. [0050] Figure 2 shows the effect of sarizotan (high doses range) on impulsivity in juvenile rats as the number of choices for the large-but-30 s-delayed reward (mean ± SEM) on control pre-drug sessions (LR(Pre)), on drug sessions (LR(Drug)) and on control post-drug sessions (LR(Post)). Statistical analysis (paired Student's t-test): difference vs. LR(Pre) a p < 0.05; difference vs. LR(Post) b p < 0.05.

[0051] Figure 3 shows the effect of sarizotan (low doses range) on impulsivity in juvenile rats as the number of choices for the large-but-30 s-delayed reward (mean ± SEM) on control pre-drug sessions (LR(Pre)), on drug sessions (LR(Drug)) and on control post-drug sessions (LR(Post)). Statistical analysis (paired Student's t-test): difference vs. LR(Pre) * p < 0.05, ** p < 0.01 , *** p < 0.001 ; difference vs. LR(Post) # p < 0.05, ## p < 0.01 , ### p < 0.001.

[0052] Figure 4 shows that at the age of 16 days, in sham (not lesioned animals) methylphenidate (3 mg/kg) increased activity while other treatments had no effect. In lesioned animals lowest dose of Sarizotan and two higher dose of methylphenidate increase activity. Please note that at this age hyperactivity is not fully developed and therefore fact that methylphenidate increases, instead if decreasing activity in lesioned animals is not surprising. Compound B = negative control (NaCI). Values are means (SEM). ^* p < 0.05 vs. vehicle (one way ANOVA followed by post-hoc test).

[0053] Figure 5 shows that at the age of 28 days, in sham (not lesioned animals) methylphenidate (3 mg/kg) increased activity while other treatments had no effect. In lesioned animals highest dose of Sarizotan and methylphenidate at 1 and 10 mg/kg decreased activity as expected from anti ADHD substance. Please note much higher increase in activity at this age produced by lesion than in 16 days old animals. Compound B = negative control (NaCI). Values are means (SEM). ^* p < 0.05 vs. vehicle (one way ANOVA followed by post-hoc test)

[0054] Figure 6 shows that at the age of 56 days, in sham (not lesioned animals) methylphenidate (3 mg/kg) increased activity while other treatments had no effect. In lesioned animals two higher doses of Sarizotan and methylphenidate at 10 mg/kg decreased activity as expected from anti ADHD substance. Compound B = negative control (NaCI). Values are means (SEM). ^* p < 0.05 vs. vehicle (one way ANOVA followed by post-hoc test) DETAILED DESCRIPTION OF THE INVENTION

[0055] The peculiarity of this invention compared to former treatment approaches for ADHD is the so far unknown therapeutic efficiency of sarizotan, which is presumably based on a unique receptor profile with several components potentiating each other in an unexpected way.

[0056] The present invention relates to the use of sarizotan and its salts, solvates and conjugates, which possesses a unique receptor profile targeting the 5-HT1a receptor and certain D2-like receptors at relevant plasma concentration. Although the activation of individual serotonergic receptors has been investigated for the treatment of ADHD, the concomitant action of a single molecule on D2-like receptors produces a so far unknown anti-ADHD effect. In theory, the unique efficacy could be achieved also through a cocktail of drugs mimicking these composite effects; however, such a cocktail of several molecules cannot successfully be developed in a clinical setting obeying regulatory requirements.

[0057] As described above, both the dopaminergic and the serotonergic system appear to play a decisive role in the development and treatment of ADHD, although it is not yet clear, which target(s) to address, and whether by agonistic and/or antagonistic agents.

[0058] Thus, in a particular embodiment the present invention relates to a method of treating ADHD in a subject in need thereof, comprising administering an effective amount of sarizotan or a pharmaceutically acceptable salt thereof, for improving the primary symptoms of ADHD, and to compositions comprising sarizotan or a pharmaceutically acceptable salt thereof for use in such treatment.

[0059] In certain embodiments, the subject in need of treatment if of an ADHD type selected from "predominantly inattentive", "predominantly hyperactive-impulsive", "combined hyperactive-impulsive and inattentive", and "not otherwise defined". [0060] The term "sarizotan" is known in the art and may also be known as EMD- 128130 or 1 -[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-([5-(4-fluoro-phenyl)-pyridin-3- yl]methyl)methanamine. As used herein, sarizotan refers to the substance, as well as its pharmaceutically acceptable salts. Sarizotan is a compound with antipsychotic effects, which has also shown a certain efficacy in reducing dyskinesias resulting from long-term anti-Parkinsonian treatment with levodopa. Sarizotan has initially been described as selective 5-HT1A receptor agonist and as general dopamine D2- like receptor antagonist (Bibbiani et al., Neurology 2001 , 57, 1829-1834; Olanow et al., Clinical Neuropharmacology 2004, 27, 58-62; Bara-Jimenez et al., Movement Disorders 2005, 20, 932-936). Later, it was found that sarizotan might be a partial agonist on D2-like receptors at higher concentrations (Bartoszyk et al., J. Neural. Transm. 2004, 111 , 113-126), and subsequently it was demonstrated that sarizotan exhibits different functional responses to these receptors, depending inter alia on the receptor (sub)type, the signaling pathway involved and the concentration, being either a partial or a full agonist at D2S, D2L, D3, D4.2 and D4.4 receptors (Kuzhikandathil and Bartoszyk, Neuropharmacology 2006, 51 , 873-884). However, in our hands sarizotan is clearly a full antagonist at the D2L, D3 and D4.4 receptors with IC50 value of 190, 210 and 31 nM, respectively. The result is somehow unexpected as compounds with efficacy for ADHD are generally assumed to have agonistic property at the D2 receptor (e.g. Fan et al. Neurobiology of Disease, 2010, 37, 228- 236).

[0061] Using radioligand displacement experiments sarizotan was also shown to interact with the 5-HT7 receptor with a K, value of 10 nM, but no mode of action can be deduced from this study (Kuzhikandathil and Bartoszyk, Neuropharmacology 2006, 51 , 873-884). To our surprise sarizotan was found to be a full agonist (EC50 value of 150 nM) and a positive allosteric modulator (inflection point IP = 90 nM) at the 5-HT7 receptor.

[0062] Some of these effects have been demonstrated in relevant animal models.

[0063] As used herein, the term "subject" encompasses mammals including animals and humans. [0064] The term "agonist" refers to a substance that binds to a receptor and mimics the cellular effect of the native or endogenous ligand for the same receptor. The term agonist includes the class of agents called full agonists, which bind and display full efficacy at the receptor, and partial agonists, which have only partial efficacy at the receptor. Partial agonists may also be seen as competitive antagonists, competing away the endogenous ligand when it is in excess or give a sub-maximal response when inadequate amount of endogenous ligand is present. The term "activation" refers to the state of a receptor when an agonist is bound to it.

[0065] The term "antagonist" refers to a substance that directly or indirectly interferes with a second substance exerting its function in its native environment. For example, an antagonist may directly compete with binding of a native or endogenous ligand to its receptor binding site, thus decreasing or blocking the cellular effect of that ligand. Alternatively, an antagonist may interfere with binding of a native or endogenous ligand to its receptor binding site, or with consequences of such ligand action by binding to an allosteric binding site on the receptor. Furthermore, a substance may act as a channel blocker, preventing the transport of a second substance to the intra- or extracellular site of action, thus blocking its respective biological function.

[0066] The term "positive allosteric modulator" refers to a substance that binds a target molecule at a binding site physically (or topographically) distinct from the binding site, where the endogenous ligand of said target binds to, and that potentiates the binding and/or signalling of the endogenous ligand.

[0067] The term "attention deficit hyperactivity disorder" or "ADHD" is a neurobehavioral developmental disorder primarily characterized by attentional problems, hyperactivity and impulsivity.

[0068] According to non-profit organization "Children and Adults with Attention Deficit/Hyperactivity Disorders" (CHADD), the following four subtypes of ADHD have been defined:

[0069] The type "predominantly inattentive" is defined as an individual experiencing at least six of the following characteristics: fails to give close attention to details or makes careless mistakes; has difficulty in sustaining attention; does not appear to listen; struggles to follow through on instructions; has difficulty with organization; avoids or dislikes requiring sustained mental effort; often loses things necessary for tasks; is easily distracted; is forgetful in daily activities

[0070] The type "predominantly hyperactive-impulsive" is defined as an individual experiencing six of the following characteristics: fidgets with hands or feet or squirms in seat; has difficulty remaining seated; runs about or climbs excessively (in adults may be limited to subjective feelings of restlessness); has difficulty engaging in activities quietly; talks excessively; blurts out answers before question have been completed; has difficulty waiting in turn taking situations; interrupts or intrudes upon others

[0071] The type "combined hyperactive-impulsive and inattentive" is defined as an individual meeting both sets of inattention and hyperactive/impulsive criteria.

[0072] The type "not otherwise defined" is defined as an individual who demonstrates some of the characteristics shown above, but an insufficient number of symptoms to reach a full diagnosis. These symptoms, however, tend to disrupt everyday life.

[0073] The term "methylphenidate" or "MPH" refers to the piperidine derivative methyl phenyl(piperidin-2-yl)acetate, which is a psychostimulant drug approved for treatment of ADHD and other diseases, and for which certain off-label uses are known as well. MPH is the active ingredient, as hydrochloride salt, of a pharmaceutical composition selected from: Ritalin^®, Ritalina®, Rilatine^®, Attenta^®, Methylin^®, Penid^®, and Rubifen^®, and the sustained release tablets Concerta^®, Metadate CD^®, Methylin^® ER, Ritalin^® LA, and Ritalin^®-SR. In these formulations, MPH is present in a racemic mixture. A pure D-enantiomer preparation is present in Focalin^®. MPH may be administered via a transdermal patch as well ((Daytrana^®).

[0074] The term "amphetamine" or "AMPH" refers to the phenylethylamine derivative (±)-1-phenylpropan-2-amine, which is a psychostimulant drug approved for treatment of ADHD and narcolepsy. AMPH is one of the active ingredients, as aspartate and or sulfate salt, and/or active metabolites of a pharmaceutical composition selected from: Adderall , Desoxyn , Dexedrine , Dextrostat , ProCentra, or Vyvanse . In these formulations, AMPH is present either as racemic mixture, or as pure D-enantiomer.

[0075] The term "treat" is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease. Thus, "treatment" as used herein includes modifying, curative and symptomatic treatments.

[0076] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition sufficient to result in a desired activity upon administration to a mammal in need thereof.

[0077] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). The term "pharmaceutically acceptable" may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0078] The term "salt" is defined as a chemical containing different charged components. The term salt also includes hydrates and solvates. Contemplated in the instant description are pharmaceutically acceptable salts, which salts may include, but are not limited to, acid addition salts, such as those made with hydrochloric, sulphuric, nitric, phosphoric, acetic, aspartic, maleic, fumaric, tartaric, citric, benzoic, methane sulphonic, naphthalene sulphonic, p-toluene sulphonic acid. All of these salts (or other similar salts) may be prepared by conventional means. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity. [0079] Sarizotan may be used according to the invention in the form of any of pharmaceutically acceptable salts, solvates and conjugates. Any references to sarizotan in this description should be understood as also referring to such salts, solvates and conjugates.

[0080] In the context of the present invention, the term "about" or "approximately" means between 90% and 110% of a given value or range.

[0081] In conjunction with the methods of the present invention, also provided are pharmaceutical compositions comprising a therapeutically effective amount of sarizotan. The compositions of the invention may further comprise a carrier or excipient (all pharmaceutically acceptable). The compositions may be formulated e.g. for once-a-day administration, twice-a-day administration, or three times a day administration.

[0082] The term "carrier" applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound (e.g., sarizotan) is administered. Such pharmaceutical carriers may be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by A.R. Gennaro, 20^th Edition.

[0083] The active ingredient (e.g., sarizotan) or the composition of the present invention may be used for the treatment of at least one of the mentioned disorders, wherein the treatment is adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., to once-a-day, twice-a-day, or three times a day administration). For this purpose the package leaflet and/or the patient information contains corresponding information.

[0084] The active ingredient (e.g., sarizotan) or the composition of the present invention may be used for the manufacture of a medicament for the treatment of at least one of the mentioned disorders, wherein the medicament is adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., to once- a-day, twice-a-day, or three times a day administration). For this purpose the package leaflet and/or the patient information contains corresponding information.

[0085] According to the present invention, the dosage form of sarizotan, or a sarizotan salt, may be a solid, semisolid, or liquid formulation according to the following.

[0086] Sarizotan may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. In another embodiment, sarizotan may be formulated as a flavored liquid (e.g., peppermint flavor). Sarizotan may be administered orally in the form of a capsule, a tablet, a melting tablet, a sugar-coated tablet, granules, pellets or the like, or as a semi-solid, or liquid formulation, e.g. in an ampoule or as a spray formulation (see Remington's Pharmaceutical Sciences, 20^th Edition, by A.R. Gennaro).

[0087] For oral administration in the form of a tablet or capsule, sarizotan may be combined with non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like.

[0088] The tablets may be coated with a concentrated sugar solution which may contain e.g., gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablets may be coated with a polymer that dissolves in a readily volatile organic solvent or mixture of organic solvents. In specific embodiments, sarizotan is formulated in immediate-release (IR) or modified-release (MR) tablets. Immediate release solid dosage forms permit the release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible. Modified release solid oral dosage forms permit the sustained release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over similarly extended time intervals and/or to modify other pharmacokinetic properties of the active ingredient. For example, sarizotan may be formulated in a modified release dosage form (including modified release tablets) to provide a dose of sarizotan.

[0089] For the formulation of soft gelatin capsules, sarizotan may be admixed with e.g., a vegetable oil or polyethyleneglycol. Hard gelatin capsules may contain granules of the active substances using either the above-mentioned excipients for tablets e.g., lactose, saccharose, sorbitol, mannitol, starches (e.g., potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug may be filled into hard gelatine capsules.

[0090] Sarizotan may also be introduced in microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA) (see, e.g., U.S. Patents Nos. 5,814,344; 5,100,669 and 4,849,222; PCT Publications Nos. WO 95/11010 and WO 93/07861). Biocompatible polymers may be used in achieving controlled release of a drug, include for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, poly(epsilon-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

[0091] Formulation of sarizotan in a semi-solid or liquid form may also be used. Sarizotan may constitute between 0.1 and 99% by weight of the formulation, more specifically between 0.5 and 20% by weight for formulations intended for injection and between 0.2 and 50% by weight for formulations suitable for oral administration.

[0092] In one embodiment of the invention, sarizotan is administered in a modified release formulation. Modified release dosage forms provide a means for improving patient compliance and for ensuring effective and safe therapy by reducing the incidence of adverse drug reactions. Compared to immediate release dosage forms, modified release dosage forms may be used to prolong pharmacologic action after administration, and to reduce variability in the plasma concentration of a drug throughout the dosage interval, thereby eliminating or reducing sharp peaks.

[0093] A modified release dosage form may comprise a core either coated with or containing a drug. The core is then coated with a release-modifying polymer within which the drug is dispersed. The release-modifying polymer disintegrates gradually, releasing the drug over time. Thus, the outer-most layer of the composition effectively slows down and thereby regulates the diffusion of the drug across the coating layer when the composition is exposed to an aqueous environment, i.e. the gastrointestinal tract. The net rate of diffusion of the drug is mainly dependent on the ability of the gastric fluid to penetrate the coating layer or matrix and on the solubility of the drug itself.

[0094] In another embodiment of the invention, sarizotan is formulated in an oral, liquid formulation. Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound. Liquid formulations may be particularly advantageous for the administration of Sarizotan to children, particularly where a daily dose is calculated on a mg/kg/day basis.

[0095] For oral administration in liquid form, sarizotan may be combined with nontoxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms. For example, solutions may contain from about 0.2% to about 20% by weight of sarizotan, with the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid formulations may contain coloring agents, flavoring agents, saccharine and carboxymethyl-cellulose as a thickening agent or other excipients.

[0096] In another embodiment, a therapeutically effective amount of sarizotan is administered in an oral solution containing a preservative, a sweetener, a solubilizer, and a solvent. The oral solution may include one or more buffers, flavorings, or additional excipients. In a further embodiment, a peppermint or other flavoring is added to the sarizotan oral liquid formulation.

[0097] For administration by inhalation, sarizotan may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0098] Solutions for parenteral applications by injection may be prepared in an aqueous solution of the compound or of a water-soluble pharmaceutically acceptable salt of the active substances, for example in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

[0099] The formulations of the invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [00100] The invention also provides a pharmaceutical pack or kit comprising one or more containers containing sarizotan and, optionally, more of the ingredients of the formulation. In a specific embodiment, sarizotan is provided as an oral solution for administration with the use of a 2-teaspoon capacity syringe (dosage KORC^®). Each oral syringe has hatch marks for measurement, with lines on the right side of the syringe (tip down) representing tsp units, and those on the left representing ml units.

[00101] The optimal therapeutically effective amount may be determined experimentally, taking into consideration the exact mode of administration, form in which the drug is administered, the indication toward which the administration is directed, the subject involved (e.g., body weight, health, age, sex, etc.), and the preference and experience of the physician or veterinarian in charge.

[00102] Dosage units for rectal application may be solutions or suspensions or may be prepared in the form of suppositories or retention enemas comprising sarizotan in a mixture with a neutral fatty base, or gelatin rectal capsules comprising the active substances in admixture with vegetable oil or paraffin oil. Rectal application as route of administration may be particularly suitable in patients unable to swallow tablets (people of younger or higher age or handicapped people).

[00103] Toxicity and therapeutic efficacy of the compositions of the invention may be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD₅o (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD50/ED50. Compositions that exhibit large therapeutic indices are preferred.

[00104] Suitable daily doses of the active ingredient of the invention in therapeutic treatment of humans are amounts up to about 3 mg per day (based on sarizotan as free base), such as from about 0.1 mg to about 3 mg, from about 0.5 mg to about 2.5 mg, from about 0.75 mg to about 2 mg, or in an amount of about 1 mg per day. In an alternative setting, the daily dose may be body weight-adjusted such as 1 mg/day up to 80 kg body weight or 1.5 mg/day for patients with a body weight of > 80 kg. Furthermore, in modified release formulations the total amount of active ingredient per day of administration could also be higher due to reduced bioavailability, e.g. up to 4 mg/day. For use of a pharmaceutically acceptable salt, a solvate, a conjugate or a derivative of sarizotan, such as sarizotan hydrochloride, the corresponding amount may be adjusted so that an equimolar amount is used. For pediatric subjects aged 4-14, and/or for patients with a body weight below about 30 kg, sarizotan may be administered at reduced amounts, for example from about 0.5 mg/day up to about 0.75 mg/day. In particular such embodiments, sarizotan is administered as an oral, liquid dosage form.

[00105] In particular embodiments, the daily dosage of sarizotan is in an amount of about 1 mg/day for patients > 30 kg, and between about 0.5 mg and about 0.75 mg/day for patients < 30 kg.

[00106] Alternatively, sarizotan may be administered on the basis of the body weight (mg/kg/day). In a particular embodiment, sarizotan or a pharmaceutically acceptable salt thereof is administered in a range from about 0.01 mg to about 0.03 mg/kg/day.

[00107] The daily doses indicated herein may be administered, for example, as one or two dosing units once, twice or three times per day, or as slow release formulation once a day. Suitable doses per dosage unit may therefore be the daily dose divided (for example, equally) between the number of dosage units administered per day, and will thus typically be about equal to the daily dose or one half, one third, one quarter or one sixth thereof. Dosages per dosage unit may thus be calculated from each daily dosage indicated herein. A daily dose of 1 mg, for example may be seen as providing a dose per dosage unit of, for example, about 1 mg, 0.5 mg, 0.33 mg, 0.25 mg and 0.16 mg, depending upon the dosing regimen chosen. In other embodiments, especially in cases where only two daily doses are administered, an unequal split of the first and the second dosage is envisaged. In such cases, for example, the first dosage comprises about 55 to 65% of the total daily dosage. For example, a daily dosage of 1 mg is split into a first dosage of 0.6 mg and a second dosage of 0.4 mg. In cases, in which more than two administration per day are envisaged, the dosage might be split also unequally, wherein the second and further dosages are reduced in comparison to the dosage before. For example, if three dosages per day are administered, the first dosage could be about one half of the total daily dosage, i.e. between about 40% to 60%, the second dosage could be about one third of the total daily dosage, i.e. between about 20% to 40%, and the third dosage could be about one sixth of the total daily dosage, i.e. between about 5% to 20%. For example, a daily dosage of 1 mg could be split into a first dosage of 0.6 mg, a second dosage of 0.3 mg and a third dosage of 0.1 mg.

[00108] Treatment duration may be short-term, e.g., several weeks (for example 8-14 weeks), until the attending physician deems further administration to be no longer necessary, but will usually be long-term due to the chronic nature of ADHD.

[00109] Sarizotan may be administered as a single anti-ADHD agent or in combination with one or more additional pharmaceutical agents for the therapy of ADHD.

[00110] The term "combination" applied to active ingredients is used herein to define at least two separate pharmaceutical compositions, each comprising an active agent (e.g. a pharmaceutical composition comprising sarizotan, and at least another pharmaceutical composition comprising another agent prescribed for the treatment of ADHD), to be administered conjointly.

[00111] Within the meaning of the present invention, the term "conjoint administration" is used to refer to administration of sarizotan, and at least one additional active agent simultaneously in different compositions, or sequentially. For the sequential administration to be considered "conjoint", however, sarizotan, and the at least one additional active agent must be administered separated by a time interval, which still permits the resultant beneficial effect for treating ADHD in a mammal.

[00112] In another embodiment, the pharmaceutical composition comprising sarizotan may further comprise at least one additional active agent as defined herein. [00113] In an additional embodiment, sarizotan is administered in combination with a drug, which increases the tolerability of the treatment with sarizotan and/or reduces at least one side effect associated with the treatment with sarizotan, such as by co-administering a drug for reducing intolerability issues derived from dopaminergic stimulation of the area postrema, particularly by co-administering domperidon.

EXAMPLES

[00114] The following example illustrates the invention without limiting its scope.

EXAMPLE 1 : Effect of sarizotan on impulsivitv in juvenile rats

[00115] Using the juvenile rat impulsivity model as preclinical model of ADHD, we demonstrated that 1 mg/kg of sarizotan was as effective as 3 mg/kg of methylphenidate in reducing impulsivity in this animal model. Based on these initial findings, we can conclude that sarizotan is a candidate for the treatment of ADHD due to its combined effect on the dopaminergic and serotoninergic system.

Materials and Methods

[00116] Animals:

Male Wistar rats (Elevage Janvier, France).

Age: Animals were born at the animal facility of the Key-Obs laboratory and kept with their dam and the whole litter until weaning, which occurred at post-natal day 21.

•Age at the beginning of conditioning: 24 days.

•At the moment of drug testing: mean: 33 days.

Body weight at the moment of the experiment (drug testing): mean: 88.9 g. Number of animals used: 55.

Experimental Design and Drug Treatment

[00117] Animals were randomly allocated to treatment groups such that the treatment groups were evenly distributed throughout the caging system.

The treatment groups and animals were arranged as indicated in Table 1. Table 1: Treatments administered before each drug session.

[00118] The animals were dosed i.p. at a constant dose volume of 2 ml dosing solution per kg of body weight, using a steel dosing cannula. The volume administered to each animal was determined each day by the weight of that animal at the time of administration.

[00119] Animals were subjected to two drug sessions, 24 h apart. Treatments indicated in Table 1 were injected i.p. 30 min before each drug session.

Behavioral Test

[00120] The experiment was conducted in a quiet dimly lit room. It was performed in four identical T-maze apparatus (Fig. 1) constructed from opaque grey plastic tubing (int. diameter: 7.5 cm), consisting of a starting runway (30 cm long), a transparent plastic box (choice area: 10 cm large, 10 cm wide, 10 cm high) and two arms (35 cm long) each leading to a rectangular black plastic goal box (18 cm large, 30 cm wide, 10 cm high). Removable grey plastic guillotine doors could be inserted into the vertical clefts, situated at the entry of the starting runway and at each end of the arms. One of the goal-boxes (left or right, depending on the rats) was constantly provided with a large reward, the other with a small reward. Large and small rewards consisted, respectively, in 5 and 1 pellets (20 mg, Technical & Scientific Equipment GmbH, Germany). The pellets were placed in a translucent food-cup before each trial. First phase: habituation.

[00121] Animals were first subjected to two to three 5-min sessions of habituation. The rat was gently introduced in the starting runway, which then was closed with a guillotine door inserted in the cleft (referred as cO in Figure 1). The animal was allowed to explore freely the apparatus and to eat food rewards placed in the food cups.

Second phase: pre-training.

[00122] After a door was placed in the cleft c2 near each goal-box, the rat was introduced in the starting runway. When it entered one of the two arms, a door was inserted behind it in the cleft c1 near the choice area and the door placed in cleft c2 was removed. As soon as the animal entered the goal-box, the door was placed again in the cleft c2. The rat was removed from the goal-box as soon as the pellets were eaten (usually in less than 1 min). The animal was then returned to its home cage for an intertrial interval of 2 to 3 min. Each rat was submitted once to three times/day to five trials sessions in this procedure. Training was initiated when the rat selected the arm giving access to the large reward at more than 14 out of 15 trials.

Third phase: training.

[00123] Rats underwent once to three times/day to five trials training sessions during which a 30 sec delay was introduced before access to the large reward. After a door was placed in the cleft c2 near each goal-box, the rat was introduced in the starting runway. When it entered one of the two arms, a second door was inserted behind it in the cleft c1 near the choice area. If the rat selected the arm leading to the large reward, it was detained in this arm for a 30 sec period -that is referred as the waiting delay- before having access to the reinforcement. Otherwise, if the animal selected the arm leading to the small reward, the door placed in the cleft c2 was immediately opened, allowing the animal to enter the goal-box. Drug testing began when the animal selected the large-but 30 sec delayed reward on no more than 20% of trials on at least three consecutive five-trials sessions.

[00124] Drug testing was conducted over six consecutive test-sessions of five trials each, during which the access to the large reward was preceded by the waiting delay. [00125] Test sessions were:

Two control pre-drug sessions: control pre-drug session 1 and control pre-drug session 2.

• Two drug sessions: drug session 1 and drug session 2.

• Two control post-drug sessions: control post-drug session 1 and control post- drug session 2.

[00126] Treatments are indicated above in Table 1. One day elapsed between drug session 1 and drug session 2. Control post-drug sessions 1 and 2 were conducted the day after drug session 2, 2 to 4 h apart. Placebo was administered before the first control pre-drug session and before the first post-drug session and the compound studied (or placebo for Vehicle group) was administered before each drug session.

[00127] The basic measure was:

LR = number of choices for the large-but-30 s-delayed reward.

For each animal, LR was calculated on:

• Control pre-drug sessions:

• LR (Pre) = number of choices for the large reward on the two control pre-drug sessions.

• LR (Pre1) = number of choices for the large reward on the first control pre-drug sessions.

• LR (Pre2) = number of choices for the large reward on the second control pre-drug sessions.

• Drug sessions:

• LR (Drug) = number of choices for the large reward on the two drug sessions.

• LR (Drugl) = number of choices for the large reward on the first drug sessions.

• LR (Drug2) = number of choices for the large reward on the second drug sessions. • Control post-drug sessions:

• LR (Post) = number of choices for the large reward on the two control post-drug sessions.

• LR (Postl) = number of choices for the large reward on the first control post-drug sessions.

• LR (Post2) = number of choices for the large reward on the second control post-drug sessions.

Then, the difference in percentage of choices between drug sessions and control sessions was calculated for each animal:

• ALR (Drug-Pre) = LR on drug sessions - LR on control pre-drug sessions.

• ALR (Drug-Post) = LR on drug sessions - LR on control post-drug sessions.

• ALR (Post-Pre) = LR on control post-drug sessions - LR on control pre-drug sessions.

Statistical Analysis

[00128] Statistical analyses were performed by using Stat View 4.5 and Excel software. Data were expressed as mean and standard error of the mean (SEM). A difference was considered as statistically significant at p< 0.05.

[00129] In a first step, the effect of treatments were analysed independently on each group (Vehicle, Methylphenidate 3 mg/kg, Sarizotan 1 mg/kg, Sarizotan 3 mg/kg and Sarizotan 10 mg/kg): the differences between LR(Pre), LR(Drug) and LR(Post) were analysed by ANOVAs for repeated measures and two-tailed Student's t-test for paired comparisons.

Results

[00130] Figure 2 shows that methylphenidate (3 mg/kg), tested as a positive reference compound, increased the number of choices for the large-but-30 s-delayed reward, indicating that experimental conditions were appropriate for detecting an improvement of the tolerance of delay of reward.

[00131] Sarizotan induced an increase in the number of choices for a large but delayed reward: This effect was observed 30 min after the injection and was significant at the three doses tested: 1 , 3 and 10 mg/kg.

This effect was still observed 24 h after the second injection for the dose of 10 mg/kg.

The effect of Sarizotan (1 and 3 mg/kg) was more prominent on the second drug session than on the first one (the difference of effect between sessions was significant at 3 mg/kg only).

Despite that Sarizotan (3 mg/kg) did not significantly increased the number of choices for the delayed reward on control post-drug sessions conducted 24 h after the injection, this parameter tended to be higher on the first than on the second post-drug session, showing that an effect of the drug could be still present.

[00132] Sarizotan also induced side effects (sedation, cry when handled, diarrhea, excessive urination) that were dose-dependent (absent at 1 mg/kg, slight at 3 mg/kg, moderate to severe at 10 mg/kg) and that were more prominent after the second injection of the highest dose than after the first one. Side effects were no more detectable 24 h after the injection.

[00133] These results showed that Sarizotan improved the tolerance of a delay of reward, i.e. reduced impulsivity in the T-maze procedure. This effect was similar to those observed with stimulant drugs (methylphenidate, D-amphetamine) and with non-stimulant noradrenaline reuptake inhibitors (desipramine, atomoxetine) (Bizot et al., Psychopharmacology 193 (2007) 215-223; Bizot et al., Neurosci. Lett. 489 (2011) 20-4). These compounds have been shown to improve ADHD symptoms, including impulsivity in ADHD patients (Durrell et al., Ann. Clin. Psychiatry 21 (2009) 26-37; Mikami et al., J. Clin. Psychol. Med. Settings 16:233-242, 2009; Pattij and Vanderschuren, Trends Pharmacol. Sci. 29 (2008) 192-199; Shiels et al., Exp. Clin. Psychopharmacol. 17 (2009) 291-301).

Conclusion

[00134] In conclusion, this study showed that Sarizotan decreased impulsivity in the T-maze procedure. These results suggest that Sarizotan may improve impulse control in ADHD patients. Impulsivity is one of the core symptoms of ADHD in addition to sustained attention deficit and hyperactivity.

EXAMPLE 2: Extending dose response curve of sarizotan in experiment

assessing impulsivity in juvenile rats.

[00135] The aim of this experiment was to verify the minimal effective dose of sarizotan on impulsivity in juvenile rats. In previous study all doses (1 , 3, 10 mg/kg) were active.

Materials and Methods

[00136] Materials, methods and the experimental setting were identical to those already described in Examplel except that lower doses were used (0.003, 0.03, 0.3 mg/kg).

Table 2: Treatments administered before each drug session.

Results

[00137] Figure 3 shows that Sarizotan decreases impulsivity in juvenile rats starting at 0.03 mg/kg and at 0.3 mg/kg effect is comparable to Methylphenidate.

[00138] In conclusion, this study suggests the potential of Sarizotan in ADHD, at least in controlling impulsivity. EXAMPLE 3: Effects of Sarizotan on Hyperlocomotion in Rats Treated

Neonatallv with 6-OHDA - Model of Hyperactivity in ADHD

[00139] The aim of this experiment was to verify whether the effect observed previously in an ADHD model of impulsivity can be extended to other symptoms of ADHD i.e. hyperactivity, using a model of neonatal treatment with 6-OHDA lesioning of the dopaminergic system.

Methods

Substances

[00140] Sarizotan (Merz Pharmaceuticals, Frankfurt Germany) and methylphenidate HCI, (Sigma-Aldrich Inc, St Louis, MO USA) were used in the study. Animals

[00141] A total of 94 male Sprague-Dawley rats were used for the study. They were the offspring of a total of 22 pregnant dams ordered from Harlan, Inc (Indianapolis, IN, USA). All animals were fed ad libitum and kept on 12:12 light/dark cycle and socially housed in plastic polycarbonate cages, which were changed at regular intervals. The facility is provided with daily monitoring of temperature (20- 22°C) and 30-60% humidity, all within the NIH Guide for Care and Use of Animals.

Treatments

[00142] At three days after birth, litters born to timed-pregnant rats were pre- treated with desipramine HCI (20 mg/kg base i.p., Tocris Bioscience, Ellisville, MO, USA). One hour later pups were individually immersed in ice for 1 min to produce cold-anesthesia. Rat pups were then placed on a flat surface under a bright light, so that cranial sutures were visible through a transparent dermis. A 26-gauge needle with polyethylene sleeve up to 2 mm from the tip was positioned 1.5 mm anterior to lambda and 2 mm lateral to the sagittal suture. Exactly 5 μΙ of vehicle [saline (0.85%) - ascorbic acid (0.1 %)] or 6-OHDA HBr (67 pg, base) was administered into each lateral ventricle. The dose of 6-OHDA consistently depletes dopamine in the striatum in adulthood by 95-99%. This procedure is described in detail (Kostrzewa and Gong, 1991 ; Brus et al., 1994). These neonatal treatments had no effect on animal survival. Rats were weaned at 21 days, then group housed in plastic cages. Only males were used for the study. [00143] Animals were randomly assigned to treatment groups. Treatment groups were evenly distributed across cages.

[00144] Two tables are provided below. Table 3 (top panel) provides information for sham animals, and Table 4 (bottom panel) provides information for animals given i.c.v. injection of 6-hydroxydopamine (6-OHDA).

Table 3: Sham Animals

Compound B = negative control (NaCI)

Table 4: Lesioned Animals

The animals were dosed i. p. at a constant dose volume of 1 ml/kg. Compound B negative control (NaCI) Experimental Methods

[00145] The day of birth was recorded as day zero (0). Three days following birth on P3, animals were given an i.c.v. injection of either saline (sham) or 6-OHDA (lesion). For habituation, on P15, all animals were i.p. administered saline to control for stress of injection and placed into the arena for 60 min. Behavioral testing began the day following habituation and sham and lesioned animals were behaviorally tested on P16, P28, and P56. On each behavioral testing day, animals were i.p. administered one of eight drug treatments: vehicle, compound B, or 0.1 , 0.3, or 1 mg/kg sarizotan or 1 , 3, or 10 mg/kg methylphenidate (MPH). Approximately 10 min after injection, animals were placed into a square arena, measuring 40 cm on a side, and the arena was painted flat black. All behavioral movements made by each animal were recorded by AnyMaze behavioral scanning software (Stoelting, Wood Dale, IL).

[00146] Approximately 10 min after each drug treatment, animals were behaviorally recorded for 30 min on each trial given at P16, P28, and P56 by a digital camera mounted approximately 2.5 m above the locomotor arena. Horizontal activity counts were used as the dependent measure. AnyMaze behavioral scanning software superimposes a digital grid over the behavioral testing arena. Each intersection animals traverse across the lines of this grid is counted as a horizontal activity count. All behavioral recording is automated as to avoid any possible experimenter bias.

Statistical Analysis

[00147] The primary statistic used was a three-way analysis of the variance (ANOVA). All post hoc comparisons were done using Fisher's LSD test (p = 0.05). The statistical software used was SPSS (Statistical Package fort he Social Sciences).

Results

[00148] The results of this study are shown in Figures 4 to 6 and show that Sarizotan decreases hyperactivity in rats with neonatal 6-OHDA lesions at the age of 28 days at 1 mg/kg and at the age of 56 days at the dose of 0.3 and 1 mg/kg. Negative control (compound B) had no effect. Conclusions

[00149] The data support the use of Sarizotan in ADHD in particular against hyperactivity. In contrast to methylphenidate, Sarizotan did not consistently increase activity in sham animals, which may be an indication for lower abuse potential.

EXAMPLE 4: Assessing in vitro Receptor Profile of Sarizotan

[00150] The aim of this experiment was to determine the receptor profile of sarizotan by performing cellular in vitro receptor functional assays.

Experimental Methods

[00151] The assays were performed by Euroscreen SA (Belgium) using Euroscreen's standard assay protocols. The studies shown in Table 5 were performed:

Table 5: Cellular Assays

Results

[00152] The results of this study are shown in Table 6 and show that sarizotan is a full agonist (EC50 value of 150 nM) and a positive allosteric modulator (inflection point IP = 90 nM) at the 5-HT7 receptor. Table 6: Receptor Results

PAM: positive allosteric modulator; XC₅o: EC₅o for agonistic activity;

antagonistic activity, and inflection point (IP) for PAM

[00153] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[00154] To the extent possible under the respective patent law, all patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

1. A pharmaceutical composition comprising sarizotan or a pharmaceutically acceptable salt thereof for use in the treatment of ADHD.

2. The pharmaceutical composition according to Claim 1 , wherein sarizotan is present as sarizotan hydrochloride.

3. The pharmaceutical composition according to claim 1 or 2, wherein sarizotan is for administration in an amount of up to 3 mg/day, particularly in a range from about 0.1 mg to about 3 mg/day, in a range from about 0.5 mg to about 2.5 mg/day, in a range from about 0.75 mg to about 2 mg/day, or more particularly in an amount of about 1 mg/day.

4. The pharmaceutical composition according to any of the preceding claims, wherein sarizotan or a pharmaceutically acceptable salt thereof is for administration once a day, twice a day (b.i.d.), or three times a day.

5. The pharmaceutical composition according to any of the preceding claims, wherein sarizotan or a pharmaceutically acceptable salt thereof is for administration in an oral formulation.

6. The pharmaceutical composition according to any of the preceding claims, wherein sarizotan or a pharmaceutically acceptable salt thereof is for administration to said subject within up to 5 hours prior to an activity requiring an increased amount of attention, and/or a reduced amount of impulsivity and/or hyperactivity.

7. The pharmaceutical composition according to any of the preceding claims, wherein sarizotan or a pharmaceutically acceptable salt thereof is for administration in combination with at least one additional pharmaceutical agent which has been shown to be effective for the treatment of ADHD.

8. The pharmaceutical composition according to claim 7, wherein said at least one additional pharmaceutical agent is selected from (i) a stimulant medication, particularly selected from the list of methylphenidate (MPH) and amphetamine (AMPH), and (ii) a non-stimulant medication, particularly selected from the list of atomoxetine, a tricyclic antidepressant, and bupropion.

9. A method of treating ADHD in a subject in need thereof, comprising the step of administering an effective amount of sarizotan or a pharmaceutically acceptable salt thereof.

10. The method according to claim 9, wherein sarizotan is present as sarizotan hydrochloride.

11. The method according to claim 9 or 10, wherein sarizotan is administered in an amount of up to 3 mg/day, particularly in a range from about 0.1 mg to about 3 mg/day, in a range from about 0.5 mg to about 2.5 mg/day, in a range from about 0.75 mg to about 2 mg/day, or more particularly in an amount of about 1 mg/day.

12. The method according to any one of claims 9 to 11 , wherein sarizotan or a pharmaceutically acceptable salt thereof is administered once a day, twice a day (b.i.d.), or three times a day.

13. The method according to any one of claims 9 to 12, wherein sarizotan or a pharmaceutically acceptable salt thereof is administered in an oral formulation.

14. The method according to any one of claims 9 to 13, wherein sarizotan or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional pharmaceutical agent which has been shown to be effective for the treatment of ADHD.

15. The method according to claim 14, wherein said at least one additional pharmaceutical agent is selected from (i) a stimulant medication, particularly selected from the list of methylphenidate (MPH) and amphetamine (AMPH), and (ii) a non-stimulant medication, particularly selected from the list of atomoxetine, a tricyclic antidepressant, and bupropion.