Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs

Definitions

• the present invention relates to the efficient treatment of an individual afflicted with Parkinson's disease (PD), the instant treatment comprising administering to the individual an effective amount of (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof.
• PD Parkinson's disease
• This invention relates to a method of treating patients afflicted with Parkinson's disease.
• Parkinson's disease is one of the most common chronic neurological diseases.
• the classical symptoms of PD are characterized by slowness of movement (bradykinesia/akinesia), rigidity and/or tremor.
• These symptoms may have an idiopathic, toxic, traumatic or genetic origin (e.g. , in Parkinson's disease (PD)) or may also occur as a consequence of treatment, e.g., with dopamine receptor antagonists in schizophrenia (Parkinson syndrome).
• Parkinson's disease is one of the most common chronic neurological diseases.
• the classical symptoms of PD are characterized by slowness of movement (bradykinesia/akinesia), rigidity and/or tremor.
• These symptoms may have an idiopathic, toxic, traumatic or genetic origin (e.g. , in Parkinson's disease (PD)) or may also occur as a consequence of treatment, e.g., with dopamine receptor antagonists in schizophrenia (Parkinson syndrome).
• Parkinson's disease is one of the
• L-DOPA levodopa
• Pamipexol dopamine receptor agonists
• non-motor symptoms are autonomic dysfunctions (cardiovascular, urinary and gastrointestinal), sleep problems, psychosis, pain, cognitive deficits and fatigue.
• autonomic dysfunctions cardiac, urinary and gastrointestinal
• sleep problems sleep problems
• psychosis psychosis
• pain cognitive deficits
• fatigue and depression have the strongest association with a decline in the quality of PD patients' life (Beiske et al., Mov Disord. 25, 2456-60, 2010; Beiske and Svensson, Acta Neurol Scand Suppl.190, 78-81 , 2010).
• Fatigue in PD is multidimensional including physical, mental and general aspects (Havlikova et al., Parkinsonism Relat Disord.14, 187-192, 2008; Havlikova et al., Eur J Neurol. 15, 475-80, 2008; Havlikova et al., J Neurol Sci. 270, 107-1 13, 2008).
• the physical dimensions of fatigue in PD are connected to problems regarding mobility and activity of daily living.
• Mental fatigue dimensions affect cognition, motivation, emotional well-being, and communication.
• general fatigue is related to bodily discomfort of the patients.
• Fatigue associated with Parkinson's disease has to be differentiated from fatigue symptoms in healthy individuals, where fatigue is a normal result of a natural reaction of body and mind to long-lasting and/or heavy burden, working, mental stress, over-stimulation or under-stimulation, jet lag, boredom, or lack of sleep.
• the physiological fatigue in healthy individuals is a normal response to physical exertion or stress, and its function is simply to protect the body from damage by overcharge.
• Such type of fatigue normally disappears spontaneously after a short recovery period. This type of fatigue isn't pathological and needs no therapeutic intervention. It is excluded from the intended medical use of the present invention.
• Only the pathological disease-oriented type of fatigue is targeted by the present invention, and, unless otherwise defined, the term "fatigue" as used herein stands for the pathological form only.
• FSS Fatigue Severity Scale
• Krupp et al. Arch Neurol. 46, 1 121-1 123, 1989.
• Each item has to be rated on a seven-grade Likert scale with a range from 1 (completely disagree) to 7 (completely agree), see Table 1.
• the total FSS score is mean score of the scores on respective 9 items.
• a total FSS score of 4 or higher present over 2 weeks prior to scoring is accepted as definition of presence of disease-oriented fatigue, especially in chronic diseases, e.g. Parkinson's disease.
• Karabanov et al. describe an open-label study of the effects of phenylpiracetam on patients suffering from PD (Karabanov et al., Atmosfera. Nervnye Bolezni 4, 29-32, 2009). In the study report, it is mentioned that fatigue was one of the parameters being monitored in the study, and a figure is presented showing a positive effect of phenylpiracetam on the combined parameter "general activity, physical and mental fatigue, asthenization symptoms”. Karabanov neither presents data on the effect of phenylpiracetam on fatigue alone, nor differentiates between disease-related fatigue and "physical" fatigue. Karabanov et al.
• Kalinskij and Nazarov describe the effect of phenylpiracetam on fatigability in the treatment of asthenic syndrome (Kalinskij and Nazarov, Zh Nevrol Psikhiatr Im SS Korsakova, 107, 61-63, 2007), and Akhapkina et al. provide additional data from a clinical study Efficacy of Phenotropil in the treatment of asthenic syndrome and chronic fatigue syndrome (Akhapkina et al., Atmosfera. Nervnye Bolezni 3, 28-31 , 2004).
• Vasilyev and Kolesnikova compared the effects of phenylpiracetam as neuroprotective therapeutic in PD to placebo treatment (Vasilyev, Y.N., and Kolesnikova, O.A., data presented at Current Issues of Experimental and Clinical Medicine, Bangkok, Pattaya, Thailand, December 20-30, 2008).
• the present invention relates to a method of improving the dopamine- replacement therapy of Parkinson's disease and/or of treating fatigue, particularly mental fatigue, associated with Parkinson's disease in a subject in need thereof, comprising the step of administering an effective amount of (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof for use in combination treatment with an agent for dopamine-replacement therapy of Parkinson's disease.
• Another aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof for use in the treatment of fatigue, particularly mental fatigue, associated with Parkinson's disease.
• the present invention relates to a method of treating fatigue associated with Parkinson's disease in a subject in need thereof, comprising the step of administering an effective amount of (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof.
• the present invention relates to a method of treating fatigue associated with Parkinson's disease in a subject in need thereof, comprising the step of administering an effective amount of (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof.
• Figure 1 shows that (R)-phenylpiracetam increases extracellular dopamine levels in rat striatum as shown by brain microdialysis.
• Figure 2 shows the concentration of (R)-phenylpiracetam in the brain, as determined by brain microdialysis, after intraperitoneal (i.p.) application.
• Affinity for DA transporter is c.a. 13 ⁇ .
• FIG. 3 shows that (R)-phenylpiracetam increases locomotor activity (horizontal activity) in rats (administration i.p. 15 min before test) ( * : p ⁇ 0.05 vs. vehicle, Kruskal- Wallis one-way ANOVA on ranks at each time interval followed by rank sum test).
• Figure 4 shows the CNS profile of (R)-phenylpiracetam in an electroencephalography (EEG) screen.
• Figure 5 shows the results from a progressive ratio test for determining the influence of (R)-phenylpiracetam on motivation in comparison to amphetamine.
• Figure 6 shows the results from a progressive ratio test for determining the influence of (R)-phenylpiracetam on motivation in comparison to methylphenidate.
• Figure 7 shows the results from a cost benefit test for determining the influence of (R)-phenylpiracetam on motivation in comparison to amphetamine.
• Figure 8 shows the results from a cost benefit test for determining the influence of (R)-phenylpiracetam on motivation in comparison to methylphenidate.
• Figure 9 shows the effect of (R)-phenylpiracetam on rotation in rats with unilateral SNc lesion (model of Parkinson's Disease).
• Figure 10 shows the effect of (R)-phenylpiracetam on rotation produced by L- DOPA in rats with unilateral SNc lesion (model of Parkinson's Disease).
• (R)- phenylpiracetam enhances L-DOPA rotations (90-150 min) but when L-DOPA effects disappear, it produces ipsilateral rotations (270-360 min). Both contra- and ipsilateral rotations indicate antiparkinsonian activity based on postsynaptic and presynaptic mechanisms, respectively.
• Figure 11 shows the effect of (R)-phenylpiracetam on dyskinesia produced by L- DOPA in rats with unilateral SNc lesion (model of Parkinson's Disease).
• (R)- phenylpiracetam did not enhance L-DOPA dyskinesia.
• Figure 12 shows the effect of (R)-phenylpiracetam on hypokinesia produced by reserpine (5 mg/kg) + alpha-methyl-p-tyrosine (250 mg/kg) (model of Parkinson's Disease).
• Figure 13 shows the effect of (R)-phenylpiracetam on hypokinesia produced by haloperidol (0.2 mg/kg) (model of Parkinson's Disease).
• Figure 14 shows that (R)-phenylpiracetam does not influence L-DOPA concentration in the brain after i.p. application as assessed using brain microdialysis.
• Figure 15 shows that L-DOPA does not influence (R)-phenylpiracetam concentration in the brain after i.p. application as assessed using brain microdialysis.
• Figure 16 shows the effect of (S)-phenylpiracetam on hypokinesia produced by haloperidol (0.2 mg/kg) (model of Parkinson's Disease) at 50 mg/kg (Fig. 14A) and at 100 mg/kg (Fig. 14B).
• the present invention relates to the use of (R)-phenylpiracetam and any of its salts, solvates and conjugates, which possesses at least an inhibitory activity on the dopamine re-uptake transporter.
• the present invention relates to a pharmaceutical composition comprising (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof for use in combination treatment with an agent for dopamine-replacement therapy of Parkinson's disease.
• phenylpiracetam refers to the compound 2-(4- phenyl-2-oxopyrrolidin-1-yl)acetamide (C12H14N2O2; MW 218.3 g/mol). Phenylpiracetam is also known as fenotropil, phenotropyl, phenotropil, fenotropyl, or carphedon and was developed in Russia, where it is available as a prescription medicine under the name "Phenotropil ® ". As used herein, phenylpiracetam refers to the substance, as well as its pharmaceutically acceptable salts.
• Phenylpiracetam is optically active and is available as a racemate of the two enantiomers.
• the International Nonproprietary Name (INN) "Fonturacetam” has been assigned to racemic phenylpiracetam.
• An international patent application with priority date in 2006 first disclosed the separation of the two enantiomers and demonstrated that the (R)-enantiomer is predominantly responsible for the pharmacological activity (WO 2007/104780).
• (R)-phenylpiracetam showed more pronounced activity in animal models for detecting antidepressant, analgesic, muscle relaxant and psychostimulant effects.
• the patent claims (R)-phenylpiracetam for the use as an antidepressant, as a stress-protective agent, as a modulator of locomotor activity, as a muscle relaxant and as an analgesic.
• phenylpiracetam was found to activate the operant behaviour, to counteract psychodepressant effects of diazepam, to inhibit post-rotational nystagmus, and to prevent the development of retrograde amnesia. It also exhibited anticonvulsant action (Bobkov et al., Biull Eksp Biol Med. 95, 50-53, 1983) and some neuroprotective activity in experimental cerebral ischemia (Tiurenkov et al., Eksp Klin Farmakol. 70, 24-29, 2007). Thus, phenylpiracetam exhibits additional pharmacological effects, which are not yet fully identified and are differentiating phenylpiracetam from other pure dopamine re-uptake transporter inhibitors.
• phenylpiracetam is administered orally and shows a half-life of 3-5 hours.
• phenylpiracetam is a nootropic drug, which has an expressed anti-amnesic action, a direct activating effect on the integrative activity of the brain, helps consolidate memory, improves concentration and mental performance, facilitates the learning process, increases the information transfer between the hemispheres of the brain, increases the resistance of brain tissue to hypoxia and toxic effects, has anticonvulsant and anxiolytic effects, regulates the processes of activation and inhibition of central nervous system, and improves mood.
• phenylpiracetam has a positive effect on the metabolism and blood circulation in brain, stimulates the redox processes and increases energy potential through utilization of glucose, improves regional blood flow in ischemic areas of the brain. It increases noradrenaline, dopamine and serotonin content in the brain, does not affect the levels of GABA, associates neither with GABAA nor GABAB receptors, has no noticeable effect on the spontaneous bioelectric activity of the brain, does not influence respiration and the cardiovascular system. It shows no significant diuretic effect and has anorexigenic effect during treatment. According to the Russian package insert, the stimulating effect of phenylpiracetam manifests in the ability to provide a moderate effect on motor responses, to enhance physical performance.
• the moderate psychostimulant effect of the drug is combined with an anxiolytic activity, and it improves mood, has some analgesic effect and raises the threshold of pain.
• the adaptogenic effect of phenylpiracetam is manifested in increasing resistance to stress in conditions of excessive mental and physical overload, fatigue, hypokinesia and immobilization, and at low temperatures.
• nootropics was created in 1960s, with the discovery of piracetam followed by pramiracetam, oxiracetam, aniracetam, tenilsetam and others, and is nowadays often used to describe cognitive enhancers that are neuroprotective and nontoxic. Most nootropics do not have a clearly defined mechanism of action and work, and seem to exert their cognitive and/or neuroprotective effects through changes in brain blood flow, energy management etc.
• (R)-phenylpiracetam appears to have a clearly defined mechanism of action by inhibition of dopamine (DA) uptake, and behavioural effects are seen at the doses that create in the brain levels within affinity for DA uptake seen in vitro and produce an increase in the DA concentration in the brain as assessed by brain microdialysis (20 ⁇ at 50 mg/kg with an affinity constant of 6 ⁇ ; see Examples).
• DA dopamine
• (R)-phenylpiracetam acts more potently in animals, which have been treated to induce symptoms resembling Parkinson ' s disease (called here diseased or parkinsonian animals) than in normal animals. Therefore (R)- phenylpiracetam appears to be more suitable to correct deficits e.g. fatigue specific for PD than general everyday fatigue.
• (R)-phenylpiracetam apparently enhances L- DOPA effects in the medium to long term range which is not due to pharmacokinetic interactions since brain levels of either L-DOPA or (R)-phenylpiracetam are not higher in animals treated with both substances as compared to single treatment.
• 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).
• 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.
• salt is defined as a chemical containing different charged components.
• salt also includes hydrates and solvates.
• (R)-Phenylpiracetam may be used according to the invention in the form of any of pharmaceutically acceptable salts, solvates and conjugates. Any references to (R)- phenylpiracetam in this description should be understood as also referring to such salts, solvates and conjugates.
• the term "dopamine-replacement therapy” refers to the principal symptomatic treatment for PD that is based upon administration of either (i) an agent replacing, or increasing the level of, endogenous dopamine (e.g., levodopa (L-DOPA)), or (ii) of a dopamine receptor agonist (e.g., apomorphine).
• an agent replacing, or increasing the level of, endogenous dopamine e.g., levodopa (L-DOPA)
• a dopamine receptor agonist e.g., apomorphine
• LID is characterised by a mixture of choreiform, dystonic or ballistic/myoclonic movements that are observed after L-DOPA administration. It is reported that about 30% of the Parkinson patients will experience dyskinesia after 4-6 years of treatment with L-DOPA while close to 90% will suffer from this complication after 9 years. Although the cause of dyskinesia remains unknown, the main risk factor for the development of LID is young age at PD onset, the disease severity and duration as well as a high initial dose of L-DOPA treatment. Ultimately, this complication severely impairs the quality of life and well-being of the patient and therefore limits the use of this drug as most important therapeutic agent.
• LID may be related to the pulsatile and intermittent nature of L-DOPA therapy.
• dopamine is formed, stored and released by the remaining dopaminergic terminals as well as by other cellular components present in the striatum such as serotoninergic neurons. Since the striatal serotonin system remains relatively spared in most PD patients, it is believed to play an important role in determining the efficacy of L- DOPA therapy.
• treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
• 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.
• treatment includes modifying, curative and symptomatic treatments.
• the term "subject” encompasses mammals including animals and humans.
• said agent is L-DOPA.
• the amount of said agent used in said combination treatment is reduced compared to the amount administered in the treatment cycle prior to said combination treatment.
• said agent is administered in said combination treatment at a reduced frequency compared to the frequency of administration in the treatment cycle prior to said combination treatment.
• said agent is L-DOPA.
• L-DOPA is administered once daily.
• (R)-phenylpiracetam is for use in a treatment comprising the following steps: (a) administering (R)-phenylpiracetam to a patient under dopamine- replacement therapy in combination with said agent administered for dopamine-replacement;
• step (c) increase of said agent once by 10% compared to the amount of said agent last administered according to step (b).
• said steps are performed in order to establish said combination treatment.
• said steps are performed in order to improve an established combination treatment.
• Another aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof for use in the treatment of fatigue, particularly mental fatigue, associated with Parkinson's disease.
• the term "fatigue associated with Parkinson's disease” refers to pathological fatigue that is independent of a type of fatigue, which is a normal response to physical exertion or stress (known as peripheral fatigue).
• This peripheral fatigue refers to muscle fatigue and is induced by repetitive muscle contractions (e.g. after athletics sports) (Chaudhuri and Behan, J Neurol Sci. 179(Suppl. 1 -2), 34-42, 2000; Chaudhuri and Behan, Lancet. 363, 978-88, 2004).
• Disease-orientated fatigue is not caused by muscle overuse or physical impairment outside the central nervous system.
• This central fatigue is a subjective feeling with symptoms of disease-associated mental fatigue (a subjective feeling of having impaired concentration, reduced memory, and speech difficulties) and disease-associated physical fatigue (subjective feeling of being exhausted and lacking energy).
• This subjective disease-associated fatigue can have its origin in particular embodiments by disturbance of the dopaminergic system of the CNS, particularly a lack of dopamine, and potentially also homeostatic changes, which lead to an abnormal degree of persistent tiredness, weakness or exhaustion.
• phenylpiracetam has apparently been prescribed inter alia for the treatment of stress associated with fatigue in healthy patients, as described in sections [0045] and [0049] above, phenylpiracetam has hitherto not been associated with the treatment of fatigue, particularly mental fatigue, associated with Parkinson's disease.
• FSS Fatigue Severity Scale
• the pharmaceutical composition is for use in the treatment of fatigue with a score on the FSS of at least 4, particular with a score of at least 4 for at least 2 weeks.
• the pharmaceutical composition is for use in the treatment of fatigue with a score on the Parkinson Fatigue Scale of at least 7.
• (R)- phenylpiracetam is present as (R)-phenylpiracetam hydrochloride.
• (R)- phenylpiracetam is for administration in a range from about 1 mg to about 250 mg/day, or in a range from about 25 mg to about 200 mg/day, or in a range from about 50 mg to about 150 mg/day.
• the term “about” or “approximately” means between 90% and 1 10% of a given value or range, i.e. "about 100” means “between 90 and 1 10". In narrower embodiments, the term “about” or “approximately” means between 95% and 105% of a given value or range, or between 98% and 102% of a given value or range, or between 99% and 101 % of a given value or range.
• (R)- phenylpiracetam or a pharmaceutically acceptable salt thereof is for administration once a day (s.i.d.), twice a day (b.i.d.), or three times a day (t.i.d.).
• (R)- phenylpiracetam or a pharmaceutically acceptable salt thereof is for administration in an oral formulation.
• (R)- phenylpiracetam 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 Parkinson's disease.
• said at least one additional pharmaceutical agent is selected from: L-DOPA, carbidopa, other types of dopamine agonists, eltoprazine, MAO-inhibitors, COMT inhibitors, and benserazide.
• said at least one additional pharmaceutical is L-DOPA, a combination of L-DOPA and carbidopa, or a combination of L-DOPA and benserazide.
• (R)- phenylpiracetam 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 fatigue, particularly mental fatigue, associated with Parkinson's disease.
• said at least one additional pharmaceutical agent is selected from: rasagiline and pramipexole.
• the present invention relates to a method of treating Parkinson's disease in a subject in need thereof, comprising the step of administering a therapeutically effective amount of (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof.
• terapéuticaally 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.
• (R)-phenylpiracetam is enhancing the efficacy of a dopamine-replacement therapy.
• said dopamine-replacement therapy is the treatment with L-DOPA.
• the treatment relates to the treatment of one or more motor symptoms of PD, particularly wearing off, on-off phenomenon, and "end-of dose" dystonia.
• the treatment relates to reducing and/or delaying the onset of levodopa-induced dyskinesia (LID).
• LID levodopa-induced dyskinesia
• the present invention relates to a method of treating fatigue associated with Parkinson's disease in a subject in need thereof, comprising the step of administering an effective amount of (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof.
• said fatigue is mental fatigue associated with Parkinson's disease.
• the invention relates to a method of treating fatigue with a score on the FSS of at least 4, particular with a score of at least 4 for at least 2 weeks.
• the invention relates to a method of treating fatigue with a score on the Parkinson Fatigue Scale of at least 7.
• the treatment of fatigue relates to the treatment of fatigue-associated symptoms in PD, particularly inactivity, motivational-deficit, floppiness, exhaustion, lassitude, and prostration.
• the present invention relates to a method of treating sleep-associated problems of PD patients, which have significant impact on their quality of life, particularly general tiredness, and drowsiness.
• (R)-phenylpiracetam may be administered as a single anti-fatigue agent or in combination with one or more additional pharmaceutical agents for the therapy of fatigue, particularly mental fatigue, associated with Parkinson's disease.
• said one or more additional pharmaceutical agents are selected from rasagiline and pramipexole.
• (R)- phenylpiracetam or a pharmaceutically acceptable salt thereof is administered in a range from about 1 mg to about 400 mg/day.
• (R)- phenylpiracetam or a pharmaceutically acceptable salt thereof is administered in a range from about 25 mg to about 350 mg/day.
• (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof is administered in a range from about 50 mg to about 300 mg/day, particularly in a range from about 50 mg to about 150 mg/day.
• (R)- phenylpiracetam or a pharmaceutically acceptable salt thereof is administered once a day, particularly about 200 mg once a day.
• (R)- phenylpiracetam or a pharmaceutically acceptable salt thereof is administered in a multiple dose, for example twice a day, or three times a day, particularly twice a day, particularly at the dose of about 100 mg twice a day.
• compositions comprising (R)-phenylpiracetam 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.
• carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound (e.g., (R)- phenylpiracetam) 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.
• the active ingredient e.g., (R)-phenylpiracetam
• 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).
• the package leaflet and/or the patient information contains corresponding information.
• the active ingredient e.g. , (R)-phenylpiracetam
• 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).
• the package leaflet and/or the patient information contains corresponding information.
• the dosage form of (R)- phenylpiracetam, or a (R)-phenylpiracetam salt may be a solid, semisolid, or liquid formulation according to the following.
• (R)-phenylpiracetam may be administered via different application routes.
• the oral and the parenteral route are the preferred route of application.
• (R)- phenylpiracetam may be formulated as a flavored liquid, a capsule or a tablet.
• (R)- phenylpiracetam may be combined with non-toxic, pharmaceutically acceptable excipients.
• 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.
• Suitable daily doses of the active ingredient of the invention in therapeutic treatment of humans are within the range from about 1 mg to about 400 mg per day (based on (R)-phenylpiracetam as free base), such as from about 25 mg to about 350 mg, or from about 50 mg to about 300 mg, particularly about 200 mg per day.
• the daily dose may be body weight-adjusted such as about 200 mg/day up to 80 kg body weight or about 240 mg/day for patients with a body weight of > 80 kg.
• (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof is administered in a range from starting from about 50 mg and increasing the dose in 50 mg steps until the desired therapeutic efficacy is reached, but maximally to about 400 mg/day.
• the total amount of active ingredient per day of administration could also be higher due to reduced bioavailability, e.g. up to about 500 mg/day.
• a pharmaceutically acceptable salt a solvate, a conjugate or a derivative of (R)- phenylpiracetam, such as (R)-phenylpiracetam hydrochloride, the corresponding amount may be adjusted so that an equimolar amount is used.
• the term “conjoint administration” is used to refer to administration of (R)-phenylpiracetam, and at least one additional active agent simultaneously in different compositions, or sequentially.
• sequential administration for the sequential administration to be considered “conjoint", however, (R)- phenylpiracetam, 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 fatigue in a mammal.
• Recombinant Chinese hamster ovary (CHO) cells CHO-K1 (ATCC ® CCL- 61TM) cells stably expressing dopamine transporters are plated.
• the cells (2 x 10 5 /ml) are pre-incubated with test compound and/or vehicle in modified Tris-HEPES buffer pH 7.1 at 25°C for 20 min and 50 nM [ 3 H]-dopamine is then added for an additional 15 min incubation period.
• Non-specific signal is determined in the presence of 10 ⁇ nomifensine.
• Cells are then solubilized with 1 % SDS lysis buffer. Reduction of [ ⁇ ]- dopamine uptake by 50 percent or more (>50%) relative to vehicle controls indicates significant inhibitory activity.
• Compounds are screened at 10, 1 , 0.1 , 0.01 and 0.001 ⁇ . These same concentrations are concurrently applied to a separate group of untreated cells and evaluated for possible compound-induced cytotoxicity only if significant inhibition of uptake is
• Recombinant Madin Darby canine kidney (MDCK) cells NBL-2) (ATCC ® CCL-34TM) expressing norepinephrine transporter are plated for two days.
• Test compound and/or vehicle is pre-incubated with cells (1 x 10 5 /ml) in modified Tris- HEPES buffer pH 7.1 for 20 min at 25°C and 25 nM [ 3 H]-norepinephrine is then added for an additional 15 min incubation period.
• a lysate is obtained from solubilized cells and counted to determine [ 3 H]-norepinephrine uptake.
• EXAMPLE 2 Assessment of (R)-phenylpiracetam on extracellular dopamine levels in rat striatum using brain microdialysis - Fig. 1
• DA Dopamine
• DOPAC 3,4-Dihydroxyphenylacetic acid
• Samples (20 ⁇ ) were injected onto the high-performance liquid chromatography (HPLC) column (Reversed Phase, particle size 3 pm, C18, Thermo BDS Hypersil column, 150 mm x 2.1 mm, Thermo Scientific, USA) by a refrigerated microsampler system, consisting of a syringe pump (Gilson, model 402, France), a multi-column injector (Gilson, model 233 XL, France), and a temperature regulator (Gilson, model 832, France).
• HPLC high-performance liquid chromatography
• Chromatographic separation was performed using a mobile phase that consisted of a NaAc buffer (6.15 g/l) with methyl alcohol (2.5% v/v), Titriplex (250 mg/l), 1-octanesulfonic acid (OSA, 150 mg/l), and adjusted with glacial acetic acid to pH 4.1 (isocratic).
• the mobile phase was run through the system at a flow rate of 0.35 ml/min by an HPLC pump (Shimadzu, model LC-10AD vp, Japan). Detection
• DA and DOPAC Concentrations of DA and DOPAC were determined in the same sample, by HPLC separation and electrochemical detection. DA and DOPAC were detected electrochemically using a potentiostate (Antec Leyden, model Intro, the Netherlands) fitted with a glassy carbon electrode set at +500 mV vs. Ag/AgCI (Antec Leyden, the Netherlands). Data was analyzed by Chromatography Data System (Shimadzu, class- vp, Japan) software. Concentrations were quantified by the external standard method.
• Siliconized guide cannula (MAB 6.14.IC) (MAB, Stockhom, Sweden) were implanted unilaterally in pentobarbital anaesthetized animals aiming at the caudatus putamen (CPu; AP: +0.1 , LM: ⁇ 2.6, DV: -3.2 mm relative to bregma; -3.3 mm interaural) according to the atlas of Paxinos and Watson (loc. cit.). Rats were given at least 3 days to recover from surgery before starting microdialysis experiments.
• Microdialysis experiments were performed in the home cage of the animal.
• a microdialysis probe (MAB 6.14.4.; 4 mm exposed membrane length, polyethersulfone (PES) membrane; MAB, Sweden) was lowered through the guide cannula into the CPu (ventral position of probe tip with reference to the skull: -7.2 mm) ca. 12 hours before the sampling and left in place for the whole testing period.
• PES polyethersulfone
• the probes were perfused with aCSF at a flow rate of 2 ⁇ /min using a CMA 102 perfusion pump (CMA, Solna, Sweden).
• the composition of the aCSF was 147 mM Na + , 2.7 mM K + , 1.2 mM Ca 2+ , 0.85 mM Mg 2+ , 0.04 mM ascorbic acid.
• the animals were connected by a head block tether system (Instech, Plymouth Meeting, USA) to a dual channel liquid swivel 375/D/22QM (Instech, Plymouth Meeting, USA). Fluorinated ethylene propylene (FEP) tubing and tubing adapters (MAB, Sweden) were used.
• FEP Fluorinated ethylene propylene
• the sample collection began one hour after start of perfusion with three 20-minutes fractions (baseline). Thereafter, each rat was injected i.p. with (R)- phenylpiracetam and/or L-DOPA (25 mg/kg + benserazide, 15 mg/kg).
• the samples (40 ⁇ ) were collected automatically with a fraction collector (CMA/142; CMA, Solna, Sweden) and stored at -20°C until analysis.
• probes were inserted into a beaker with aCSF (37°C) containing 100 nM solution of (R)-phenylpiracetam or L-DOPA.
• Five samples (40 ⁇ ) were collected while only the last 2 were used for analysis of (R)- phenylpiracetam or L-DOPA concentration.
• HPLC in combination with atmospheric pressure ionization tandem mass spectrometry (API-MS/MS) was employed (HPLC (Shimadzu Prominence, Duisburg, Germany) coupled to an API 4000 Q Trap (triple quadrupole, Applied Biosystems/MDS Sciex, Darmstadt, Germany) equipped with a Turbolonspray source (ESI)).
• the analytical column was an Onyx Monolithic C18 50 mm x 2 mm (Phenomenex, Aillesburg, Germany).
• the mobile phase consisted of the eluent A water and eluent B acetonitrile both containing 0.1 % of formic acid.
• the chromatographic run consisted of a gradient over 1.5 min from 5% acetonitrile in water at start until a mobile phase composition of 50 % acetonitrile in water. A volume of 1 ml was injected in the API/MS/MS. A standard curve was used to calculate sample concentrations of studied agents in our samples.
• Figure 3 shows that (R)-phenylpiracetam increases locomotor activity (horizontal activity) in rats starting at the dose of 100 mg/kg indicating stimulatory activity.
• (R)-Phenylpiracetam was tested at four different concentrations (1 mg/kg, 12.5 mg/kg, 25 mg/kg, and 50 mg/kg) in an EEG screen as described by Dimpfel (Dimpfel, Neuropsychobiology, 58 (2008)178-86).
• the animals were allowed to acclimatize for at least 4 weeks before the study started. There was automatic control of light cycle, temperature and humidity. Light hours were 18 h in the evening - 6 h in the morning. Daily monitoring indicated that temperature and humidity remained within the target ranges of 22 ⁇ 2°C and 44 ⁇ 5% respectively. Cages, bedding, and water bottles were changed at regular intervals, i.e. every 2-3 days. Standard diet (Nohrlin H10, Altromin, D-32791 Heil, Germany) was available to the animals ad libitum. The animals had access to domestic quality mains water ad libitum.
• Rats were implanted with 4 bipolar concentric steel electrodes within a stereotactic surgical procedure during anaesthesia with ketamine. All four electrodes were placed 3 mm lateral within the left hemisphere. Dorsoventral coordinates were 4, 6, 4.2 and 8 mm and anterior coordinates were 3.7, 9.7, 5.7 and 12.2 mm for frontal cortex, striatum, hippocampus, and reticular formation, respectively (according to the atlas of Paxinos and Watson, 1982).
• a pre-constructed base plate carrying 4 bipolar stainless steel semi-micro electrodes (neurological electrodes "SNF 100" from Rhodes Medical Instruments, Inc., Summerland, CA 93067, USA) and a 5-pin-plug was fixed to the skull by dental cement interacting with 3 steel screws placed on distance into the bone.
• the distant recording spot of the electrode was the active electrode whereas the proximal spots of the four electrodes were connected to each other to give a reference.
• the base plate was carrying a plug to receive later on the transmitter (weight: 5.2 g including battery, 26 mm x 12 mm x 6 mm of size).
• EEG signals were recorded from frontal cortex, hippocampus, striatum and reticular formation of freely moving rats from inside a totally copper shielded room. Signals were wirelessly transmitted by a radio-telemetric system (Rhema Labortechnik, Hofheim, Germany, using 40 MHz as carrier frequency) and were amplified and processed as described earlier to give power spectra of 0.25 Hz resolution (Dimpfel et al. 1986; Dimpfel et al. 1988; Dimpfel et al. 1989; Dimpfel, 2003). In short, after automatic artifact rejection signals were collected in sweeps of 4 s duration and fast- fourier transformed using a Hanning window. Sampling frequency was 512 Hz.
• (R)-Phenylpiracetam produced a dose dependent attenuation of alpha2 and betal waves. The highest dosage produced a different pattern of changes in that theta power increases within the frontal cortex were observed. Motility was increased. Alpha2 waves are mainly under the control of dopamine (Dimpfel, loc. cit.). Thus, direct or indirect effects on dopaminergic neurotransmission can be expected from (R)- phenylpiracetam. Attenuation of alpha2 and betal waves has also been observed after administration drugs used for treatment of M. Parkinson (Dimpfel and Hoffmann, Neuropsychobiology, 62, 213-20, 2010). In summary (R)-phenylpiracetam shows a profile within the area of stimulatory drugs. EXAMPLE 6: Effect of (R)-phenylpiracetam in motivation tests - Figs. 5, 6, 7, 8 Test Item
• Methylphenidate purchased from Sigma (Taufkirchen, Germany) was dissolved in distilled water fresh for each test day.
• Modafinil purchased from Sequoia Research Products Limited (Pangbourne, UK) was dissolved in 1 % w/v methylcellulose (Sigma, Taufmün, Germany) in 0.9% NaCI water fresh for each test day.
• (R)- Phenylpiracetam was dissolved in distilled water fresh for each test day.
• Test 1 Progressive ratio (PR) task
• Behavioral testing was conducted in 12 operant test chambers (Med Associates, St. Albans, USA). Each chamber was equipped with a retractable lever, a food dispenser with receptacle, an overhead house light and two stimulus lights, one above the lever and the other above the food receptacle. An infrared photocell beam detected nose pokes into the food receptacle.
• the apparatus was controlled by a computer system (SmartControl®-lnterface and Med PC-software, Med Associates, St. Albans, USA). The light above the food receptacle indicated the delivery of a food pellet in the receptacle. Rats were first habituated to the operant boxes for two sessions (30 min each) on two consecutive days.
• a session lasted for 90 min or was ended when a rat failed to press the lever for consecutive 10 min.
• the value of the last completed ratio (breaking point) was recorded as well as the amount of received rewards, the perseverative lever presses, the duration of the session and the latency to respond.
• Animals of all treatment groups received respective vehicle/drug infusions 30 min pre-test on the final two sessions involving testing under a PR schedule.
• the rats had the choice between working for their preferred food (Bioserve pellets) by pressing the lever on a PR schedule as described above or obtaining lab chow being freely available in a dish (about 15 g) within the operant chamber.
• the food receptacle and the lever were positioned on the same wall of the operant chamber, the dish containing the lab chow was situated in a corner on the opposite side of the operant chamber.
• a session lasted for 90 min or ended when a rat failed to press the lever for consecutive 10 min. Thereafter the amount of lab chow ingested was calculated. Animals of all treatment groups received vehicle/drug infusions 30 min p re-test.
• (R)-Phenylpiracetam was tested in rats with unilateral SNc lesions - a preclinical model of Parkinson's disease. In some experiments it was combined with L- DOPA.In this model, ipsilateral rotations indicate a presynaptic mode of action, which is consistent with inhibition of dopamine uptake as a primary mode of action. L-DOPA produced contralateral rotations.
• (R)-Phenylpiracetam was injected i.p. in saline.
• L-DOPA 25 mg/kg
• benserazide 5 mg/kg
• Rats were injected with substance, placed in Perspex cylinders (30 cm diameter), and the rotational behaviour (360°) was scored for 120 min at 20-min intervals using TSA rotation measurement system.
• EXAMPLE 8 Effect of (R)-phenylpiracetam on L-DOPA-induced dyskinesia - Fig.
• AIMs abnormal involuntary movements
• the locomotor activity was measured in four perspex boxes (ENV-515-16, 43.2 cm x 43.2 cm x 30 cm), Med-Associates Inc. system) equipped with 4 arrays of 16 infrared photobeams placed 3 cm above the box floor. Distance travelled (DT) was used in further analysis for measuring locomotion. The recording started immediately after placing animals in the open field.
• the locomotor activity was measured in four perspex boxes (ENV-515- 16, 43.2 cm x 43.2 cm x 30 cm), Med-Associates Inc. system) equipped with 4 arrays of 16 infrared photobeams placed 3 cm above the box floor. Distance travelled (DT) was used in further analysis for measuring locomotion. The recording started immediately after placing animals in the open field.

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