EP3411025A1 - Nouvelles thérapies combinées contre les troubles neurologiques - Google Patents

Nouvelles thérapies combinées contre les troubles neurologiques

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Publication number
EP3411025A1
EP3411025A1 EP17705044.0A EP17705044A EP3411025A1 EP 3411025 A1 EP3411025 A1 EP 3411025A1 EP 17705044 A EP17705044 A EP 17705044A EP 3411025 A1 EP3411025 A1 EP 3411025A1
Authority
EP
European Patent Office
Prior art keywords
acamprosate
piperazin
phenylsulfonyl
quinolone
baclofen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP17705044.0A
Other languages
German (de)
English (en)
Inventor
Daniel Cohen
Serguei Nabirotchkin
Rodolphe HAJJ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharnext SA
Original Assignee
Pharnext SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharnext SA filed Critical Pharnext SA
Priority claimed from PCT/EP2017/052470 external-priority patent/WO2017134280A1/fr
Publication of EP3411025A1 publication Critical patent/EP3411025A1/fr
Pending legal-status Critical Current

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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
    • A61K31/33—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • 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
    • 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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to new combinations and methods for the treatment of neurological diseases and disorders. More specifically, the present invention relates to novel combinatorial therapies of neurological disorders, based on 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline, baclofen and/or acamprosate combinations.
  • AD Alzheimer's disease
  • dysphasia language disorder in which there is an impairment of speech and of comprehension of speech
  • dyspraxia disability to coordinate and perform certain purposeful movements and gestures in the absence of motor or sensory impairments
  • agnosia inability to recognize objects, persons, sounds, shapes, or smells attributable to involvement of the cortical association areas.
  • Special symptoms such as spastic paraparesis (weakness affecting the lower extremities) can also be involved [1-4].
  • AD Alzheimer's disease
  • Memory impairment is the early feature of the disease and involves episodic memory (memory for day-today events). Semantic memory (memory for verbal and visual meanings) is involved later in the disease. By contrast, working memory (short-term memory involving structures and processes used for temporarily storing and manipulating information) and procedural memory (unconscious memory that is long-term memory of skills and procedure) are preserved until late. As the disease progresses, the additional features of language impairment, visual perceptual and spatial deficits, agnosias and apraxias emerge. The classic picture of AD is sufficiently characteristic to allow identification in approximately 80% of cases [7]. Nevertheless, clinical heterogeneity does occur which is important for clinical management but also provides further implication of specific medication treatments for functionally different forms [8].
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • amyloid cascade hypothesis states that the neurodegenerative process is a series of events triggered by the abnormal processing of the Amyloid Precursor Protein (APP) [12]
  • APP Amyloid Precursor Protein
  • neuronal cytoskeletal degeneration hypothesis proposes that cytoskeletal changes are the triggering events.
  • amyloid cascade hypothesis states that the amyloid cascade hypothesis [14-16] and AD researchers have mainly focused on determining the mechanisms underlying the toxicity associated with Abeta proteins.
  • AD Alzheimer's disease
  • NMDAR NMD A glutamate Receptors
  • Acetylcholinesterase inhibitors such as donepezil, rivastigmine, tacrine and galantamine are currently available in the market and are efficient in symptomatic relief with beneficial effects on cognitive, functional and behavioral symptoms [26].
  • NMDAR antagonists that target various sites of this receptor have been tested to counteract excitotoxicity.
  • Uncompetitive NMDAR antagonists target the ion channel pore thus reducing the calcium entry into postsynaptic neurons. Only one of them, namely memantine, reached the approval status in moderate to severe AD. This molecule is however of limited benefit in most AD patients, because it has only modest symptomatic effects and further has shown no significant effects in mild Alzheimer's disease [27,28].
  • Furthermore many other NMDAR antagonists have failed in advanced clinical trials for several neurodegenerative disorders [24,29,30].
  • Another approach in limiting excitotoxicity consists in inhibiting the presynaptic release of glutamate.
  • WO2009/133128, WO2009/133141, WO2009/133142, WO2011/054759, and WO2012/117076 disclose drug combinations suitable for use in the treatment of AD.
  • WO2012/117076 particularly discloses the therapeutic efficacy of baclofen-acamprosate combination in AD, including for the protection of glutamate toxicity and/or Abeta toxicity.
  • 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline is a selective 5-HT6 receptor antagonist that has shown some efficacy in treating AD and is currently under clinical trial as an add-on therapy for donepezil.
  • WO2003/080580, WO2005/026125, WO2009/074607 disclose 3-phenylsulfonyl- 8-(piperazin-l-yl) quinoline based compositions suitable for use in treating central nervous system diseases.
  • the present invention provides new therapeutic methods and compositions suitable for treating neurological disorders, particularly associated with neuronal cell death and cognitive decline. More particularly, the invention relates to compositions comprising 3-phenylsulfonyl-8- (piperazin-l-yl) quinoline in combination with baclofen and/or acamprosate, as well as to the use thereof for treating neurological disorders related to glutamate excitotoxicity and/or amyloid beta (Abeta) toxicity and/or ischemic stress and/or oxidative stress.
  • 3-phenylsulfonyl-8- (piperazin-l-yl) quinoline in combination with baclofen and/or acamprosate
  • Abeta amyloid beta
  • the invention stems, inter alia, from the unexpected discovery, by the inventors, that the combination of 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline with baclofen and/or acamprosate particularly strongly protects neuronal cells from various stresses e.g., Abeta toxicity, glutamate toxicity, oxidative stress or ischemic stress, which underlie various neurological disorders.
  • combinations of 3-phenylsulfonyl-8-(piperazin- 1 -yl) quinolone with baclofen and/or acamprosate constitute an efficient treatment for patients suffering from, predisposed to, or suspected to suffer from neurological disorders.
  • An object of this invention therefore relates to compositions comprising (i) 3- phenylsulfonyl-8-(piperazin-l-yl) quinoline and (ii) baclofen and/or acamprosate.
  • Another object of this invention relates to compositions comprising 3-phenylsulfonyl-8-
  • a particular object relates to compositions comprising 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline, baclofen and acamprosate.
  • compositions comprising:
  • the compounds in the combinations of the invention may be formulated separately or together. Also, they may be administered simultaneously, separately, sequentially or subsequently to a subject. They can also be administered repeatedly to a subject.
  • compositions of the invention typically further comprise one or several pharmaceutically acceptable excipients or carriers.
  • the compounds as used in the present invention may be in the form of a salt, hydrate, ester, ether, acid, amide, racemate, isomer, enantiomerically pure composition or conjugates. They may also be in the form of sustained- release formulations. Prodrugs or derivatives of the compounds may be used as well.
  • a compound is used as such or in the form of a salt, hydrate, ester, ether or sustained release form thereof.
  • a particularly preferred salt for use in the present invention is acamprosate calcium.
  • a prodrug or derivative is used.
  • a further object of this invention is a method of preparing a pharmaceutical composition, the method comprising mixing 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone with baclofen and/or acamprosate in a pharmaceutically acceptable excipient or carrier.
  • this method comprises mixing 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline, baclofen and acamprosate in a pharmaceutically acceptable excipient or carrier.
  • a further object of the invention relates to compositions or combinations as defined above for use in the treatment of a neurological disorder, particularly Alzheimer's disease (AD), an AD related disorder, Parkinson's disease (PD), Lewy body dementia, multiple system atrophy and other related synucleinopathies, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, spinal cord injury (SCI), epilepsy, traumatic brain injury or a brain ischemic event.
  • AD Alzheimer's disease
  • PD Alzheimer's disease
  • PD Parkinson's disease
  • Lewy body dementia dementia
  • multiple system atrophy and other related synucleinopathies Huntington's disease (HD), amyotroph
  • Another object of this invention relates to a method for treating a neurological disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising administering to said subject an effective amount of a composition or combination as defined above.
  • a further object of this invention relates to a method for treating AD or an AD related disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising administering to said subject an effective amount of a composition or combination as defined above.
  • a preferred object of this invention relates to a method for treating a neurological disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising simultaneously, separately, sequentially or subsequently administering to said subject an effective amount of 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, and baclofen and/or acamprosate.
  • this method comprises simultaneously, separately, sequentially or subsequently administering to said subject an effective amount of 3-phenylsulfonyl-8-(piperazin- 1-yl) quinoline, baclofen and acamprosate.
  • a more preferred object of this invention relates to a method for treating AD or an AD related disorder in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising simultaneously, separately, sequentially or subsequently administering to said subject an effective amount of 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, and baclofen and/or acamprosate.
  • Another preferred object of this invention relates to a method for treating PD or Lewy body dementia, multiple system atrophy and another related synucleinopathy in a mammalian subject in need thereof, preferably a human subject in need thereof, the method comprising simultaneously, separately, sequentially or subsequently administering to said subject an effective amount of 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline, and baclofen and/or acamprosate.
  • the invention may be used for treating a neurological disorder in any mammalian subject, preferably in any human subject, at any stage of the disease.
  • the compositions of the invention are able to ameliorate the pathological condition of said subjects.
  • FIGS. 1A-1B Effect of combination of 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline, baclofen and acamprosate in an in vivo model of cognitive impairment induced by ⁇ 2 5 -3 5 toxicity. Cognitive impairment was assessed with respect to spatial working memory ( Y-maze test - figure 1 A) and contextual long-term memory (step-through passive avoidance - figure I B).
  • Groups were as follows: (1) Sc.A 2 5- 3 5; (2) ⁇ 25 -35; (3) ⁇ 25 -35 / 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline (lmg/Kg); (4) ⁇ 2 5-35 / baclofen and acamprosate (respectively 0.480m g/ g and 0.032mg/Kg); and (5) ⁇ 25-3 5 / 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline (lmg/Kg), baclofen and acamprosate (respectively 0.480mg/Kg and 0.032mg/Kg). Data arc represented as mean and SEM.
  • the present invention provides new methods and compositions for treating neurological disorders.
  • the invention discloses novel active compound combinations which allow an effective correction of such diseases and may be used in any mammalian subject. More particularly, the invention provides novel compositions comprising 3- phenylsulfonyl-8-( piperazin- 1 -yl) quinoline. baclofen and/or acamprosate. As illustrated in the examples, the presence of 3-phenylsulfonyl-8-( piperazin- 1 -yl) quinoline surprisingly increases the neuroprotective effect of baclofen or acamprosate or of combinations of baclofen and acamprosate against Abeta oligomer toxicity, glutamate excitotoxicity.
  • oxidative stress induced by 6 01 IDA and ischemic stress is therefore suited for treating any neurological disorders, particularly disorders which involve nerves and/or neurons injuries, beta-amyloid, glutamate excitotoxicity. oxidative stress, ischemic stress and/or cognitive impairment such as neurodegenerative diseases.
  • An object of the invention therefore resides in a composition or compositions comprising, consisting essentially of or consisting of: 3-phenylsulfonyl-8-(piperazin-l-yl) quinoline or a pharmaceutically acceptable salt, hydrate, derivative, isomer, racemate, or prodrug thereof, of any chemical purity, and baclofen and/or acamprosate, or a pharmaceutically acceptable salt, hydrate, derivative, isomer, racemate, or prodrug thereof, of any chemical purity.
  • compositions comprising, consisting essentially of or consisting of:
  • acamprosate or a pharmaceutically acceptable salt, hydrate, derivative, isomer, racemate, or prodrug thereof, of any chemical purity.
  • Neurodepsy refers to diseases including Alzheimer's disease (AD), an AD related disorder, Parkinson's disease (PD), Lewy body dementia, multiple system atrophy and other related synucleinopathies, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, spinal cord injury (SCI), epilepsy, traumatic brain injury or a brain ischemic event.
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • Lewy body dementia dementia
  • multiple system atrophy and other related synucleinopathies Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, spinal cord injury (SCI), epilepsy, traumatic brain injury or a brain ischemic event.
  • HD amyotrophic lateral sclerosis
  • MS multiple s
  • AD related disorder includes senile dementia of AD type (SDAT), frontotemporal dementia (FTD), vascular dementia, mild cognitive impairment (MCI) and age-associated memory impairment (AAMI).
  • SDAT senile dementia of AD type
  • FDD frontotemporal dementia
  • MCI mild cognitive impairment
  • AAMI age-associated memory impairment
  • treatment includes the therapy, prevention, prophylaxis, retardation or reduction of symptoms provoked by or of the causes of the above diseases or disorders.
  • treatment includes in particular the control of disease progression and associated symptoms.
  • treatment particularly includes a protection against i) the toxicity caused by beta amyloid (Abeta), or a reduction or retardation of said toxicity, and/or ii) a protection against glutamate excitotoxicity, or a reduction or retardation of said toxicity, and/or iii) a protection against 6-OHDA toxicity or a reduction or retardation of said toxicity and/or iv) a protection against ischemic stress or a reduction or retardation of cell mortality under said stress.
  • beta amyloid Abeta
  • ii a protection against glutamate excitotoxicity
  • a reduction or retardation of said toxicity and/or iii) a protection against 6-OHDA toxicity or a reduction or retardation of said toxicity and/or iv) a protection against ische
  • treatment particularly designates an improvement of cognitive symptoms or a protection of neuronal cells.
  • combinatorial treatment/therapy designates a treatment wherein 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone and at least baclofen and/or acamprosate are coadministered to a subject to cause a biological effect.
  • the compounds may be administered together or separately, at the same time, sequentially or subsequently.
  • 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone and baclofen and/or acamprosate may be administered through different routes and protocols.
  • the combination therapy comprises the simultaneous administration of the compounds, as a single formulation.
  • the combination therapy comprises the separate administration of 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, on the one hand, and baclofen and acamprosate, on the other hand.
  • the combination therapies of the invention also encompass "add-on" therapies, where the subject is already under treatment with some (one or more) of the compounds of a combination of the invention, and the treatment comprises administering the other(s).
  • the combination treatment of the invention comprises administering baclofen and/or acamprosate to the subject.
  • a specific drug or compound is meant to include not only the specifically named molecule, but also any pharmaceutically acceptable salt, hydrate, derivative, isomer, racemate, enantiomerically pure composition, conjugate, or prodrug thereof, of any chemical purity.
  • prodrug refers to any functional derivatives (or precursors) of a compound of the present invention, which, when administered to a biological system, generates said compound as a result of e.g., spontaneous chemical reaction(s), enzyme catalysed chemical reaction(s), and/or metabolic chemical reaction(s).
  • Prodrugs typically have the structure X-drug wherein X is an inert carrier moiety and drug is the active compound.
  • the prodrug is devoid of activity or less active than the drug and the drug is released from the carrier in vivo.
  • Prodrugs are usually inactive or less active than the resulting drug and can be used, for example, to improve the physicochemical properties of the drug, to target the drug to a specific tissue, to improve the pharmacokinetic and pharmacodynamic properties of the drug and/or to reduce undesirable side effects.
  • Some of the common functional groups that are amenable to prodrug design include, but are not limited to, carboxylic, hydroxyl, amine, phosphate/phosphonate and carbonyl groups.
  • Prodrugs typically produced via the modification of these groups include, but are not limited to, esters, carbonates, carbamates, amides and phosphates. Specific technical guidance for the selection of suitable prodrugs is general common knowledge [31-35].
  • prodrugs may be performed by conventional methods known by those skilled in the art. Methods which can be used to synthesize other prodrugs are described in numerous reviews on the subject [31-38]. For example, arbaclofen placarbil is listed in ChemID plus Advance database (website: chem.sis.nlm.nih.gov/chemidplus/) and arbaclofen placarbil is a well-known prodrug of baclofen [39,40].
  • derivative of a compound includes any molecule that is functionally and/or structurally related to said compound, such as an acid, amide, ester, ether, acetylated variant, hydroxylated variant, or an alkylated (C1-C6) variant of such a compound.
  • derivative also includes structurally related compound having lost one or more substituent as listed above. For example, homotaurine is a deacetylated derivative of acamprosate.
  • Preferred derivatives of a compound are molecules having a substantial degree of similarity to said compound, as determined by known methods.
  • derivatives should have a Tanimoto similarity index greater than 0.4, preferably greater than 0.5, more preferably greater than 0.6, even more preferably greater than 0.7 with a parent drug.
  • the Tanimoto similarity index is widely used to measure the degree of structural similarity between two molecules.
  • Tanimoto similarity index can be computed by software such as the Small Molecule Subgraph Detector [42,43] available online (http://www.ebi.ac.uk thornton-srv/software/SMSD/).
  • Preferred derivatives should be both structurally and functionally related to a parent compound, i.e., they should also retain at least part of the activity of the parent drug, more preferably they should have a protective activity against Abeta toxicity and/or glutamate toxicity and/or ischemic stress and/or oxidative stress, and or impairment of cognitive function.
  • derivative also includes metabolites of a drug, e.g., a molecule which results from the (biochemical) modification(s) or processing of said drug after administration to an organism, usually through specialized enzymatic systems, and which displays or retains a biological activity of the drug. Metabolites have been disclosed as being responsible for much of the therapeutic action of the parent drug.
  • a "metabolite” as used herein designates a modified or processed drug that retains at least part of the activity of the parent drug, preferably that has a protective activity against Abeta toxicity and/or glutamate toxicity and/or ischemic stress and/or oxidative stress, and or impairment of cognitive function.
  • salt refers to a pharmaceutically acceptable and relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • Pharmaceutical salt formation consists in pairing an acidic, basic or zwitterionic drug molecule with a counterion to create a salt version of the drug.
  • a wide variety of chemical species can be used in neutralization reaction.
  • Pharmaceutically acceptable salts of the invention thus include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of acetic acid, nitric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid.
  • Pharmaceutically acceptable salts of the invention also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, or choline salts. Though most of salts of a given active principle are bioequivalent, some may have, among others, increased solubility or bioavailability properties.
  • Salt selection is now a common standard operation in the process of drug development as taught by Stahl and Wermuth in their handbook [44] .
  • the designation of a compound is meant to designate the compound per se, as well as any pharmaceutically acceptable salt, hydrate, isomer, racemate, isomer, enantiomerically pure composition, ester or ether thereof.
  • the designation of a compound is meant to designate the compound as specifically designated per se, as well as any pharmaceutically acceptable salt thereof.
  • a sustained-release formulation of a compound is used.
  • Table 1 Illustrative CAS numbers for baclofen, acamprosate and 3-phenylsulfonyl-8-(piperazin-l- yl) quinolone are provided in Table 1 below. Table 1 cites also, in a non- limitative way, common salts, racemates, isomers, enantiomerically pure compositions, prodrugs, metabolites or derivatives of the compounds according to the invention.
  • prodrugs of baclofen are given in Hanafi [45], particularly baclofen esters and baclofen ester carbamates, which are of particular interest for central nervous system targeting. Hence such prodrugs are particularly suitable for compositions of this invention.
  • Arbaclofen placarbil as mentioned before is also a well-known prodrug and may thus be used instead of baclofen in compositions of the invention.
  • baclofen can be found in the following patent applications: WO2010102071, US2009197958, WO2009096985, WO2009061934, WO2008086492, US2009216037, WO2005066122, US2011021571, WO2003077902 and WO2010120370, that can be used instead of baclofen in the compositions of the invention.
  • Useful prodrugs for acamprosate such as pantoic acid ester neopentyl sulfonyl esters, neopentyl sulfonyl esters prodrugs or masked carboxylate neopentyl sulfonyl ester prodrugs of acamprosate are notably listed in WO2009033069, WO2009033061, WO2009033054 WO2009052191, WO2009033079, US 2009/0099253, US 2009/0069419, US 2009/0082464, US 2009/0082440 and US 2009/0076147, that can be used instead of acamprosate in the compositions of the invention.
  • Preferred combinations of the invention comprise one of the following drug combinations, for combined, separate, sequential or subsequent administration:
  • the drug combinations of the invention have a strong unexpected effect on several biological processes involved in neurological disorders.
  • the inventors have surprisingly discovered that these new compositions can simultaneously, in a synergistic manner, attenuate Abeta toxicity, re-establish disturbed glutamate signaling, attenuate oxidative stress, attenuate ischemic stress in affected neurons, and/or attenuate or reverse impairment of cognitive functions.
  • the exampled showed that in a combination therapy of the invention, 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone when combined with a combination of baclofen and acamprosate, efficiently and synergistically reversed the impairment of cognitive functions induced by ⁇ (25-35) toxicity.
  • AD and AD related disorders such as AD and AD related disorders, MS, ALS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events.
  • the present invention therefore proposes a novel therapy of neurological disorders, based on combinations of 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone with baclofen and/or acamprosate. More particularly, the present invention proposes a novel therapy of AD and AD related disorders, MS, ALS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events, based on combinations of 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone with baclofen and/or acamprosate.
  • the invention relates to a composition comprising 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone with baclofen and/or acamprosate for use in the treatment of AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events.
  • the invention relates to one of the following compositions comprising, consisting essentially of or consisting of :
  • the invention relates to one of the following combinations of compounds:
  • the compounds can be administered separately, simultaneously, sequentially or subsequently to the subject.
  • the invention relates to the use of 3-phenylsulfonyl-8-(piperazin- 1-yl) quinolone with baclofen and/or acamprosate for the manufacture of a medicament for the treatment of AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events.
  • the invention relates to the use of these combinations or compositions for treating AD or an AD related disorder in a subject in need thereof.
  • the invention relates to the use of these combinations or compositions for treating MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events in a subject in need thereof.
  • combination therapies of the invention comprising at least 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone and baclofen and/or acamprosate show in vitro a very efficient ability to protect neuronal cells from Abeta oligomers toxicity and/or glutamate excitotoxicity and/or 6-OHDA induced oxidative stress and/or ischemic stress.
  • AD and AD related disorders such as AD and AD related disorders, MS, ALS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events for treating cognitive symptoms associated with such disorders.
  • compositions of the invention are also efficient in synergistically protecting neuronal cells from the above stresses underlying the neurological disorders and improve clinical symptoms such as cognitive impairment in known mice model of cognitive malfunction.
  • Synergy can be proven through different ways, for instance, by calculating a combinatory index from dose-effect curves of each of the compounds alone and of their combinations [46-48] and/or using the factorial ANOVA test with treatments as factors, indicating whether an interaction between the factors is significant [49]. Synergy may be assessed by methods known by those skilled in the art.
  • An object of this invention thus also resides in a composition or compositions as defined above for treating a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events.
  • a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events.
  • the invention is particularly suited for treating AD and AD related disorders, as shown in the experimental section by the results related to Abeta oligomer toxicity and glutamate toxicity, and to a less extend to the results related to less specific stresses as oxidative ischemic stresses.
  • An object of this invention thus also resides in a composition as defined above for treating AD or an AD related disorders further comprising at least one drug selected from are tacrine (CAS: 321-64-2), donepezil (CAS: 120014-06-4), galantamine (CAS: 357-70-0; 1953-04-4), rivastigmine (CAS: 123441-03-2) or memantine (CAS: 19982-08-2).
  • the invention relates to one of the following compositions per se comprising, consisting essentially of or consisting of:
  • compositions comprising, consisting essentially of or consisting of::
  • the invention relates to one of the following combinations of compounds comprising, consisting essentially of or consisting of::
  • the invention is also particularly suited for treating PD, as disclosed in the experimental section by the results related to 6-OHDA toxicity in dopaminergic neurons, glutamate toxicity and ischemic stress.
  • An object of this invention thus also resides in a composition as defined above for treating PD further comprising levodopa or levodopa and carbidopa.
  • the invention relates to one of the following compositions per se comprising, consisting essentially of or consisting of:
  • compositions comprising, consisting essentially of or consisting of:
  • the invention relates to one of the following compositions comprising, consisting essentially of or consisting of:
  • the invention relates to one of the following combinations of compounds comprising, consisting essentially of or consisting of:
  • the invention relates to one of the following combinations of compounds comprising, consisting essentially of or consisting of:
  • the compounds or drugs may be formulated together or separately, and administered together, separately, sequentially or subsequently.
  • a further object of this invention resides in the use of a composition or a combination as defined above for the manufacture of a medicament for treating a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events.
  • a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events.
  • the invention further provides a method for treating a neurological disorder such as AD,
  • AD related disorders MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events comprising administering to a subject in need thereof an effective amount of a composition or combination as disclosed above.
  • a further object of the invention is a method of treating a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events, the method comprising simultaneously, separately, sequentially or subsequently administering to a subject in need thereof an effective amount of a combination as disclosed above.
  • a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events
  • a further object of the invention is a method of treating a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events, the method comprising subsequently administering to a subject in need thereof and already treated with 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, an effective amount of baclofen and/or acamprosate.
  • a further object of the invention is a method of treating a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events
  • the invention relates to a method of treating a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events, in a subject in need thereof, comprising administering simultaneously, separately, sequentially or subsequently to the subject an effective amount of 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone and baclofen and/or acamprosate.
  • a neurological disorder such as AD, AD related disorders, MS, PD, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events
  • compositions of the invention typically comprise one or several pharmaceutically acceptable carriers or excipients.
  • the drugs or compounds are usually mixed with pharmaceutically acceptable excipients or carriers.
  • a further object of this invention is a method of preparing a pharmaceutical composition, the method comprising mixing the above compounds in an appropriate excipient or carrier.
  • the method comprises mixing 3-phenylsulfonyl-8-(piperazin- 1-yl) quinolone, baclofen and acamprosate in an appropriate excipient or carrier.
  • the compounds are used as such or in the form of a pharmaceutically acceptable salt, prodrug, derivative, or sustained/controlled release formulation thereof.
  • the combination therapy of the invention may further be used in conjunction or association or combination with additional drugs or treatments beneficial to treating neurological condition in the subjects.
  • Other therapies used in conjunction with drug(s) or drug(s) combination(s) according to the present invention may comprise one or more drug(s) that ameliorate symptoms of MS, Lewy body dementia, multiple system atrophy and other related synucleinopathies, ALS, HD, peripheral neuropathies, alcoholism or alcohol withdrawal, neurological manifestations of drug abuse or drug abuse withdrawal, SCI, epilepsy, traumatic brain injury or brain ischemic events, or drug(s) that could be used for palliative treatment of these disorders.
  • illustrative therapies which can be used with combinations of the invention are tacrine (CAS: 321-64-2), donepezil (CAS: 120014- 06-4), galantamine (CAS: 357-70-0; 1953-04-4), rivastigmine (CAS: 123441-03-2) or memantine (CAS: 19982-08-2) for AD and AD related disorders, or lisuride (CAS: 140387-89-9, 1189731- 50-7, 14611-52-0, 14611-51-9), rasagiline (CAS: 136236-51-6), tolcapone (CAS: 134308-13-7), entacapone (CAS: 130929-57-6), clozapine (CAS: 5786-21-0), desipramine (CAS: 50-47-5), citalopram (CAS: 59729-33-8), nortriptyline (CAS: 72-69-5), paroxetine (CAS: 61869-08-7), atomoxetine (CAS: 82248-59-7), venla
  • Therapy according to the invention may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital, so that the doctor can observe the therapy's effects closely and make any adjustments that are needed.
  • the duration of the therapy depends on the stage of the disease being treated, age and condition of the patient, and how the patient responds to the treatment.
  • the dosage, frequency and mode of administration of each component of the combination can be controlled independently.
  • one compound may be administered orally while the second compound may be administered intramuscularly.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recovery from any as yet unforeseen side- effects.
  • the compounds may also be formulated together such that one administration delivers all drugs.
  • each compound of the combination may be by any suitable means that results in a concentration of the compound that, combined with the other component(s), is able to ameliorate the patient condition and/or efficiently treat the disease or disorder.
  • compositions include those suitable for oral, rectal, topical (including transdermal, buccal and sublingual), or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the invention further includes a pharmaceutical formulation, as herein before described, in combination with packaging material suitable for said formulations.
  • a formulation for the combination treatment can be inferred by instructions, facilities, provisions, adaptations and/or other means to help using the formulation most suitably for the treatment.
  • Such measures make a patient pack specifically suitable and adapted for use for treatment with the combinations of the present invention.
  • the compound(s) may be contained, in any appropriate amount, in any suitable carrier substance.
  • the compound(s) may be present in an amount of up to 99% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy [50] and the Encyclopedia of Pharmaceutical Technology [51]).
  • compositions according to the invention may be formulated to release the active compound(s) substantially immediately upon administration or at any predetermined time or time period after administration.
  • the sustained/controlled release formulations include (i) formulations that create a substantially constant concentration of the compound within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the compound within the body over an extended period of time; (iii) formulations that sustain compound action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance; (iv) formulations that localize compound action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that target compound action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.
  • Administration of drugs in the form of a sustained/controlled release formulation is especially preferred in cases in which the drug has (i) a narrow therapeutic index (i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)); (ii) a narrow absorption window in the gastro -intestinal tract; or (iii) a very short biological half-life so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
  • a narrow therapeutic index i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)
  • LD50 median lethal dose
  • ED50 median effective dose
  • Controlled release may be obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the compound is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner (single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes).
  • Formulations for oral use include tablets containing the composition of the invention in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives
  • Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.
  • the tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the active compound substance in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active compound substance until after passage of the stomach (enteric coating).
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).
  • a time delay material such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active drug substance).
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology [51].
  • Drugs/compounds may be mixed together in the tablet, or may be partitioned.
  • a first compound is contained on the inside of the tablet, and a second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound.
  • Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, liquid paraffin, or olive oil.
  • Powders, granulates, micro- or nano-particles may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner.
  • Controlled release compositions for oral use may, e.g., be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance.
  • Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of drugs, or by incorporating the drug into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • a controlled release composition containing one or more of the drugs of the claimed combinations may also be in the form of a buoyant tablet or capsule (i.e., a tablet or capsule that, upon oral administration, floats on top of the gastric content for a certain period of time).
  • a buoyant tablet formulation of the drug(s) can be prepared by granulating a mixture of the drug(s) with excipients and 20-75% w/w of hydrocolloids, such as hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose. The obtained granules can then be compressed into tablets. On contact with the gastric juice, the tablet forms a substantially water- impermeable gel barrier around its surface. This gel barrier takes part in maintaining a density of less than one, thereby allowing the tablet to remain buoyant in the gastric juice.
  • Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration.
  • Formulation as a suspension provides the active ingredient in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and the like.
  • composition(s) may also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • injection, infusion or implantation intravenous, intramuscular, subcutaneous, or the like
  • suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • compositions for parenteral use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added (see below).
  • the composition may be in form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • the composition may include suitable parenterally acceptable carriers and/or excipients.
  • the active compound(s) may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release.
  • the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents.
  • compositions according to the invention may be in the form suitable for sterile injection.
  • a parenterally acceptable liquid vehicle water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate).
  • a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like.
  • Controlled release parenteral compositions may be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, or emulsions.
  • the active compound(s) may be incorporated in biocompatible carriers, liposomes, nanoparticles, implants, or infusion devices.
  • Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactia poly- (isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamnine).
  • Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies.
  • Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(glycolic acid) or poly(ortho esters)).
  • suitable dosage forms for a composition include suppositories (emulsion or suspension type), and rectal gelatin capsules (solutions or suspensions).
  • the active compound(s) are combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols.
  • an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols.
  • additives, enhancers, or surfactants may be incorporated.
  • compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes.
  • the formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters, and other kinds of transdermal drug delivery systems.
  • the pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel- forming agents, ointment bases, perfumes, and skin protective agents.
  • the preservatives, humectants, penetration enhancers may be parabens, such as methyl or propyl p-hydroxybenzoate, and benzalkonium chloride, glycerin, propylene glycol, urea, etc.
  • compositions described above for topical administration on the skin may also be used in connection with topical administration onto or close to the part of the body that is to be treated.
  • the compositions may be adapted for direct application or for application by means of special drug delivery devices such as dressings or alternatively plasters, pads, sponges, strips, or other forms of suitable flexible material.
  • any of the compounds of the combinatorial therapy of the invention may be used in slow release formulations, and/or formulated with agents that modify tissue distribution or bioavailability. More particularly, when applicable, one or more compound(s) of the therapy of the invention are formulated with drug eluting polymer or biomolecules or micelles or liposome- forming lipids or oil in water emulsions, or pegylated or solid nanoparticles or microparticles for oral or parenteral or intrathecal administration to modify tissue distribution or bioavailability.
  • formulating agents include PGA, PLGA, cyclodextrins, albumin or protein carriers, nano and microparticles, liposomes, emulsions, and PEG.
  • the compounds may be associated in pharmaceutical compositions in different ways. They may be mixed together as separate entities. They may be formulated separately. They may also be linked, covalently or non-covalently, with or without a linker. In a particular embodiment, at least two compounds are linked, preferably through a cleavable or non-cleavable linker. Dosages and duration of the treatment
  • the drugs/compounds of the combination(s) may be administered concomitantly, either in the same or different pharmaceutical formulation, sequentially or subsequently. If there is sequential or subsequent administration, the delay in administering the second (or additional) active ingredient should not be such as to lose the benefit of the efficacious effect of the combination of the active ingredients.
  • a minimum requirement for a combination according to this description is that the combination should be intended for combined use with the benefit of the efficacious effect of the combination of the active ingredients.
  • the intended use of a combination can be inferred by facilities, provisions, adaptations and/or other means to help using the combination according to the invention.
  • Therapeutically effective amounts of the compounds in a combination of this invention include, e.g., amounts that are effective for reducing AD symptoms, halting or slowing the progression of the disease once it has become clinically manifest, or prevention or reduction of the risk of developing the disease.
  • the active drugs of the present invention may be administered in divided doses, for example two or three times daily. Moreover, different frequency of administration may be used for each compound, e.g., one compound may be administered once daily whereas the other compounds may be administered twice daily.
  • a single administration of a composition of 3- phenylsulfonyl-8-(piperazin-l-yl) quinolone per day, associated with a twice daily administration of a composition of baclofen and acamprosate is preferred.
  • a single daily dose of each compound in the combination is preferred, with a single daily dose of all drugs in a single pharmaceutical composition (unit dosage form) being most preferred.
  • Administration can be repeated for several days to several years, and may even be for the life of the patient. Chronic or at least periodically repeated long-term administration is indicated in most cases.
  • administration can also be once every two days, three to two days per week or once weekly. There also, different frequency of administration may be used for each compound.
  • unit dosage form refers to physically discrete units (such as capsules, tablets, loaded syringe cylinders, shaker cups, ampoule) suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material or materials calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • the amount of each drug in a preferred unit dosage composition depends upon several factors including the administration method, the body weight and the age of the patient, the stage of the disease, the risk of potential side effects considering the general health status of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect the dosage used.
  • each drug in the combination will usually lie within the range of doses not above the dosage usually prescribed for long-term maintenance treatment or proven to be safe in phase 3 clinical studies.
  • One remarkable advantage of the invention is that each compound may be used at low doses in a combination therapy, while producing, in combination, a substantial clinical benefit to the patient.
  • the combination therapy may indeed be effective at doses where the compounds have individually low or no effect.
  • a particular advantage of the invention lies in the ability to use sub-optimal doses of each compound, i.e., doses which are lower than therapeutic doses usually prescribed, preferably 1/2 of therapeutic doses, more preferably 1/3, 1/4, 1/5, 1/6, 1/7, 1/8, 1/9 or even more preferably 1/10 of therapeutic doses.
  • doses as low as 1/20, 1/30, 1/50, 1/100, or even lower, of therapeutic doses are used.
  • the compounds would exhibit lower to no side effect, while the combination(s) according to the invention are fully effective in treating neurological disorders.
  • a preferred dosage corresponds to amounts from 1 % up to 50% of those usually prescribed for long-term maintenance treatment.
  • the most preferred dosage may correspond to amounts from 1% up to 10% of those usually prescribed for long-term maintenance treatment.
  • therapies of the invention also comprise administering donepezil, memantine, rivastigmine, tacrine, or galantamine or levodopa
  • these drugs are used either at their usual dose and regimen (i.e. as an add-on therapy) or even at a lower dose, from 1% up to 50% of those usually prescribed in their respective indications.
  • - acamprosate between 0.0 ⁇ g and 1000 mg/day, preferably less than 400 mg/day, preferably less than 200 mg/day, more preferably less than 100 mg/day, even more preferably less than 50 mg/day, preferably less than 1 mg/day, preferably less than 0.5 mg/day, preferably less than 10 ⁇ g/day, more preferably less than ⁇ g/day, even more preferably less than O. ⁇ g/day such dosages being particularly suitable for oral administration.
  • - baclofen between 0.000 ⁇ g/day and 150 mg/day, preferably less than 100 mg/day, more preferably less than 50 mg/day, even more preferably less than 25 mg/day, preferably less than 1 mg/day, preferably less than 0.5 mg/day, preferably less than 10 ⁇ g/day, preferably less than ⁇ g/day, preferably less than O. ⁇ g/day, more preferably less than 0.0 ⁇ g/day, even more preferably less than 0.001 ⁇ g/day such dosages being particularly suitable for oral administration.
  • - 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone between 0.5 and 75 mg/day, preferably less than 35 mg/day, preferably less than 17 mg/day, more preferably less than 5 mg/day, even more preferably less than 1 mg/day, such dosages being particularly suitable for oral administration.
  • - donepezil between 0.5 and 23 mg/day, preferably less than 10 mg/day, more preferably less than
  • - memantine between 0.5 and 20 mg/day, preferably less than 10 mg/day, more preferably less than 5 mg/day even more preferably less than 2 mg/day, such dosages being particularly suitable for oral administration.
  • - tacrine between 0.4 and 160 mg/day, preferably less than 80 mg/day, more preferably less than 40 mg/day, even more preferably less than 20 mg/day, such dosages being particularly suitable for oral administration.
  • - rivastigmine between 0.3 and 12 mg/day, preferably less than 6 mg, more preferably less than 3 mg/day.
  • - galantamine between 0.8 and 24 mg/day, preferably less than 12 mg, more preferably less than
  • - levodopa between 0.1 and 6 g per day, preferably less than 3 g per day, more preferably less than lg per day, even more preferably less than 500 mg per day.
  • compositions can be formulated to provide per oral dose between:
  • - acamprosate between 0.0 ⁇ g and 1000 mg, preferably less than 400 mg, preferably less than 200 mg, more preferably less than 100 mg, even more preferably less than 50 mg, preferably less than 1 mg, preferably less than 0.5 mg, preferably less than 10 ⁇ g, more preferably less than ⁇ ⁇ g, even more preferably less than O. ⁇ g such dosages being particularly suitable for oral administration;
  • - baclofen between 0.0001 ⁇ g and 150 mg, preferably less than 100 mg, more preferably less than 50 mg, even more preferably less than 25 mg, preferably less than 1 mg, preferably less than 0.5 mg, preferably less than 10 ⁇ g, preferably less than ⁇ g, preferably less than O. ⁇ g, more preferably less than O.O ⁇ g, even more preferably less than O.OO ⁇ g such dosages being particularly suitable for oral administration;
  • - donepezil between 0.5 and 23 mg, preferably less than 10 mg, more preferably less than 5 mg even more preferably less than 2 mg, such dosages being particularly suitable for oral administration;
  • - memantine between 0.5 and 20 mg, preferably less than 10 mg, more preferably less than 5 mg even more preferably less than 2 mg, such dosages being particularly suitable for oral administration;
  • - tacrine between 0.4 and 160 mg, preferably less than 80 mg, more preferably less than 40 mg, even more preferably less than 20 mg, such dosages being particularly suitable for oral administration;
  • - rivastigmine between 0.3 and 12 mg, preferably less than 6 mg, more preferably less than 3 mg; - galantamine between 0.8 and 24 mg, preferably less than 12 mg, more preferably less than 6 mg even more preferably 3 mg, and/or
  • compositions of the invention can be formulated to comprise, as active ingredient:
  • - acamprosate in an amount from between O.OO ⁇ g to 16 mg/kg of human subject, preferably less than 7 mg/ kg of human subject, preferably less than 4 mg/ kg of human subject, more preferably less than 2 mg/ kg of human subject, even more preferably less than 1 mg/ kg of human subject, preferably less than 0.2 mg/ kg of human subject, preferably less than 0.1 mg/ kg of human subject, preferably less than 0.2 ⁇ g/ kg of human subject, more preferably less than 0.02 ⁇ g/ kg of human subject y, even more preferably less than 0.002 ⁇ g/ kg of human subject such dosages being particularly suitable for oral administration;
  • - baclofen in an amount from between 0.000002 ⁇ g and 3 mg/ kg of human subject, preferably less than 2 mg/ kg of human subject, more preferably less than 1 mg/ kg of human subject, even more preferably less than 0.5 mg/ kg of human subject, preferably less than 0.02 mg/ kg of human subject, preferably less than 0.01 mg/ kg of human subject, preferably less than 0.2 ⁇ g/ kg of human subject, preferably less than 0.02 ⁇ g/ kg of human subject, preferably less than 0.002 ⁇ g/ kg of human subject, more preferably less than 0.0002 ⁇ g/ kg of human subject, even more preferably less than 0.00002 ⁇ g/ kg of human subject such dosages being particularly suitable for oral administration;
  • - donepezil in an amount from between 0.01 to 0.4 mg/ kg of human subject, preferably less than 0.2 mg/ kg of human subject, more preferably less than 0.1 mg/ kg of human subject even more preferably less than 0.04mg/ kg of human subject, such dosages being particularly suitable for oral administration;
  • - memantine in an amount from between 0.01 and 0.4 mg/kg of human subject, preferably less than 0.2 mg/ kg of human subject, more preferably less than 0.1 mg/ kg of human subject even more preferably less than 0.04 mg/ kg of human subject, such dosages being particularly suitable for oral administration;
  • - tacrine in an amount from between 0.006 to 2.7mg/ kg of human subject, preferably less than 1.3 mg/ kg of human subject, more preferably less than 0.7mg kg of human subject, even more preferably less than 0.4mg/ kg of human subject, such dosages being particularly suitable for oral administration;
  • - rivastigmine in an amount between 0.005 to 0.2 mg/ kg of human subject, preferably less than 0.1 mg kg of human subject, more preferably less than 0.005 mg/ kg of human subject;
  • - galantamine in an amount between 0.013 to 0.4 mg/ kg of human subject, preferably less than 0.2 mg/kg of human subject, more preferably less than O.lmg/ kg of human subject even more preferably 0.05mg/ kg of human subject; and/or
  • - levodopa in an amount between 0.016 to 0.1 g/kg of human subject, preferably less than 0.5 g/kg of human subject, more preferably less than 0.017g/ kg of human subject, even more preferably less than 10 mg/ kg of human subject.
  • baclofen and acamprosate may be used in different ratios, e.g., at a weight ratio acamprosate/baclofen comprised between 0.05 and 1000 (w/w), preferably between 0.05 and 100 (w/w), more preferably between 0.05 and 50 (w/w).
  • the amount of the compounds actually administered will be determined by a physician, in the light of the relevant circumstances including the condition or conditions to be treated, the exact composition to be administered, the age, weight, and response of the patient, the severity of the patient's symptoms, and the chosen route of administration. Therefore, the above dosage ranges are intended to provide general guidance and support for the teachings herein, but are not intended to limit the scope of the invention.
  • Rat cortical neurons are cultured as described by Singer et al. [52]. Briefly pregnant female rats of 15 days gestation were killed by cervical dislocation (Rats Wistar) and the foetuses were removed from the uterus. The cortex was removed and placed in ice-cold medium of Leibovitz (L15) containing 2% of Penicillin 10.000 U/ml and Streptomycin 10 mg/ml and 1% of bovine serum albumin (BSA). Cortices were dissociated by trypsin for 20 min at 37 °C (0.05%). The reaction was stopped by the addition of Dulbecco's modified Eagle's medium (DMEM) containing DNasel grade II and 10%> of fetal calf serum (FCS).
  • DMEM Dulbecco's modified Eagle's medium
  • Cells were then mechanically dissociated by 3 serial passages through a 10 ml pipette and centrifuged at 515 x g for 10 min at +4 °C. The supernatant was discarded and the pellet of cells was re-suspended in a defined culture medium consisting of Neurobasal supplemented with B27 (2%), L-glutamine (0.2 mM), 2% of PS solution and 10 ng/ml of BDNF. Viable cells are counted in a Neubauer cytometer using the trypan blue exclusion test.
  • the cells are seeded at a density of 30 000 cells/well in 96 well-plates (wells were pre-coated with poly-L-lysine (10 ⁇ g/ml)) and are cultured at +37°C in a humidified air (95%)/C02 (5%) atmosphere.
  • ⁇ -42 peptide is reconstituted in define culture medium at 40 ⁇ (mother solution) and was slowly shaken at +37 °C for 3 days in dark.
  • the control medium is prepared in the same conditions.
  • test compounds and combinations thereof are solved in culture medium (+0.1% DMSO) and then pre-incubated with neurons for one hour before the ⁇ - 42 application (in a final volume per culture well of 100 ⁇ ).
  • 100 ⁇ of ⁇ -42 peptide is added to a final concentration of 10 ⁇ diluted in presence of drug(s), in order to avoid further test compound(s) dilutions.
  • Cortical neurons are intoxicated for 24 h.
  • Three separate cultures are performed per condition, 6 wells per condition.
  • BDNF 50 ng/ml
  • Three separate cultures are performed per condition, 12 wells per condition.
  • MAP-2 mouse monoclonal antibody anti microtubule-associated-protein 2
  • Alexa Fluor 488 goat anti-mouse IgG (Molecular probe) at the dilution of 1/400 in PBS containing 1% fetal calf serum and 0.1% of saponin for 1 H at room temperature. For each condition, 30 pictures per well are taken using InCell AnalyzerTM 1000 (GE Healthcare) with 20x magnification. All images are taken with the same conditions. Analysis of total neurite network and number of neurons is performed automatically by using Developer software (GE Healthcare). Data processing
  • Results show that tested combinations are efficient in protecting neuronal cells against ⁇ -42 toxicity (Table 2). Of note, these combinations show an effective protective effect on neuronal cells at doses where 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, baclofen, acamprosate, rivastigmine, galantamine, tacrine, memantine or donepezil when used alone show no or a marginal protective effect.
  • Table 2
  • Glutamate toxicity is involved in the pathogenesis of numerous neurological diseases or disorders such as multiple sclerosis, Alzheimer's Disease, AD related disorders, amyotrophic lateral sclerosis, Parkinson's Disease, Lewy body dementia, multiple system atrophy or PD related synucleinopathies, Huntington's Disease, neuropathies, alcoholism or alcohol withdrawal, neurological manifestation of drug abuse or drug abuse withdrawal, epilepsy, traumatic brain injury or a brain ischemic event or spinal cord injury.
  • the drugs are first tested individually, followed by assays for their combinatorial action. In this set of experiments, compounds have been tested for their ability to prevent or reduce the toxic effects of glutamate on neuronal cells.
  • the efficacy of drug combinations of the invention is assessed on primary cortical neuron cells.
  • the neuroprotective effect of compounds is assessed by quantification of the neurite network (Neurofilament immunostaining (NF)) which specifically reveals the glutamatergic neurons.
  • NF Neuroofilament immunostaining
  • drugs of the candidate combinations are solved in culture medium (+0.1% DMSO).
  • Candidate combinations and drugs are then pre-incubated with neurons for 1 hour before the glutamate injury.
  • glutamate is added for 20 min, to a final concentration of 40 ⁇ , in presence of candidate combinations, in order to avoid further drug dilutions.
  • medium is changed with medium with candidate combination but without glutamate.
  • the culture is fixed 24 hours after glutamate injury.
  • MK801 dizocilpinehydrogen maleate, 77086-22-7 - 20 ⁇
  • Nuclei of cells are labeled by a fluorescent marker (Hoechst solution, SIGMA), and neurite network quantified. Six wells per condition are used to assess neuronal survival in 3 different cultures.
  • Oxygen and glucose deprivation assays (in vitro model of ischemia)
  • the neuroprotective effect of compounds or combinations thereof is assessed by quantification of the neurite network (Neurofilament immunostaining (NF)) using MAP2 antibody.
  • NF Neuroofilament immunostaining
  • Riluzole a neuroprotective drug, (Riluteck ® , 5 ⁇ ) is used as positive control.
  • candidate drugs are solved in culture medium (+0.1% DMSO) and then pre-incubated with neurons for 1 hour before the oxygen and glucose deprivation.
  • culture medium (+0.1% DMSO)
  • the medium is removed and fresh medium without glucose is added.
  • This medium is composed by DMEM without glucose (Invitrogen) supplemented with 2% B27, 0.2 mM L-glutamine, 1% PS solution, 10 ng ml of BDNF.
  • the cells are transferred into an anaerobic incubator with 95 % N 2 and 5 % CO2 at 37°C.
  • MAP2 mouse monoclonal primary antibody against MAP2 (MAP2, Sigma). These antibodies are revealed with Alexa Fluor 488 goat anti- mouse IgG (Molecular probe).
  • Nuclei of cells are labelled by a fluorescent marker (Hoechst solution, SIGMA). Six wells per condition are used to assess neuronal survival in 3 different cultures.
  • 6-hydroxydopamine (6-OHDA) is a neurotoxic drug which selectively destroys dopaminergic neurons by generating reactive oxygen species and inducing mitochondrial death in the cells. Because of this nervous cell specificity, 6-OHDA toxicity is commonly used in vitro and in vivo to study Parkinsonism. Notwithstanding, a protective activity against oxidative stress and energy deprivation induced by 6-OHDA does show that combinations of the invention are efficient in protecting nervous cells from oxidative stress and energy deprivation that occur in other neurological disorders as multiple sclerosis, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's Disease, Huntington's Disease, neuropathies, alcoholism or alcohol withdrawal, or spinal cord injury.
  • Rat dopaminergic neurons are cultured as described by Schinelli et al. [53]. Pregnant female rats of 15 days gestation are killed by cervical dislocation (Rats Wistar; Janvier) and the foetuses removed from the uterus. The embryonic midbrains are removed and placed in ice- cold medium of Leibovitz (L15; PanBiotech) containing 2% of Penicillin-Streptomycin (PS; PanBiotech) and 1% of bovine serum albumin (BSA; PanBiotech). Only the ventral portions of the mesencephalic flexure are used for the cell preparations as this is the region of the developing brain rich in dopaminergic neurons.
  • the midbrains are dissociated by trypsinisation for 20 min at 37°C (Trypsin EDTA IX; PanBiotech). The reaction is stopped by the addition of Dulbecco's modified Eagle's medium (DMEM; PanBiotech) containing DNAase I grade II (0.1 mg/ml; PanBiotech) and 10% of foetal calf serum (FCS; Invitrogen). Cells are then mechanically dissociated by 3 passages through a 10 ml pipette and centrifuged at 180 x g for 10 min at +4°c on a layer of BSA (3.5%) in L15 medium.
  • DMEM Dulbecco's modified Eagle's medium
  • FCS foetal calf serum
  • the supernatant is discarded and the cells of pellet are re-suspended in a defined culture medium consisting of Neurobasal (Invitrogen) supplemented with B27 (2%; Invitrogen), L-glutamine (2 mM; PanBiotech) and 2% of PS solution and 10 ng/ml of Brain-derived neurotrophic factor (BDNF, PanBiotech) and 1 ng/ml of Glial-Derived Neurotrophic Factor (GDNF, PanBiotech). Viable cells are counted in a Neubauer cytometer using the trypan blue exclusion test.
  • the cells are seeded at a density of 40 000 cells/well in 96 well-plates (pre-coated with poly-L-lysine (Greiner)) and are cultured at 37°C in a humidified air (95%) /C02 (5%) atmosphere. Half of the medium is changed every 2 days with fresh medium. Five to six percents of the neuronal cell population are dopaminergic neurons. 6-OHDA and tests compounds exposure
  • test compounds are pre-incubated for lh before the 6-OHDA application during 48 hours.
  • End point evaluation measure of total number of TH positive neurons
  • a neuroprotective effect is observed for combinations of the invention in TH neurons survival test after 48 h 6-OHDA injury on dopaminergic neurons. As shown in Table 5 below, all of the claimed drug combinations have a protective effect against 6-OHDA injury in dopaminergic neuronal cells. Table 5
  • Combinations of Table 5 show an effective protective effect against 6-OHDA injury in dopaminergic neuronal cells in comparison to the protective effect of the drug when used alone 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, baclofen, acamprosate, donepezil, memantine, tacrine, rivastigmine, galantamine.
  • the peptide amyloidosis ( ⁇ 25-35) is the hydrophobic part of the full-length amyloid peptide. Injection of this peptide in the brain ventricles of rodents is known to induce a progressive neurodegenerative processes resulting in cognitive impairments. This model is commonly used for diseases involving cognitive impairment symptoms. The results showed that a combination of 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, baclofen and acamprosate were not only efficient but had a synergistic effect in protecting treated animals from the neurodegenerative processes due to the injection of toxic peptides. Treatment protocol
  • mice Male Swiss mice were administered from Day 0 to Day 10 with sham product (group 1 and 2); 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone (group 3); baclofen and acamprosate (group 4); or 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone, baclofen and acamprosate (group 5).
  • 3-phenylsulfonyl-8-(piperazin-l-yl) quinolone) was administered orally by gavage once a day (lmg/Kg of the individual body weight of each mouse.
  • a composition of baclofen and acamprosate was administered orally by gavage twice a day (respectively 48C ⁇ g/Kg and 32 ⁇ g/ g of the individual body weight of each mouse).
  • oligomeric ⁇ 25-35 peptide was injected ICV (intracerebroventricular) to provoke amyloid toxicity (group 2, 3, 4 and 5).
  • Sc.A peptide was injected ICV as negative control of oligomeric ⁇ 2 5-35 peptide ICV injections (group 1).
  • mice Male Swiss mice were anesthetized with isoflurane 2.5% and were injected ICV with ⁇ 2 5-35 peptide (9 nmol/mouse) or Sc.Ap peptide (9 nmol/mouse), in a final volume of 3 ⁇ /mouse, according to the previously described method (Maurice et al, 1996, 1998; Meunier et al, 2006, 2013; Villard et al, 2009, 2011).
  • the Y-maze is made of grey polyvinylchloride. Each arm is 40 cm long, 13 cm high, 3 cm wide at the bottom, 10 cm wide at the top, and converging at an equal angle. Each mouse was placed at the end of one arm and allowed to move freely through the maze during an 8 min session. The series of arm entries, including possible returns into the same arm, was checked visually. An alternation was defined as entries into all three arms on consecutive occasions. The number of maximum alternations was therefore the total number of arm entries minus two and the percentage of alternation was calculated as (actual alternations / maximum alternations) x 100. Parameters included the percentage of alternation (memory index) and total number of arm entries (exploration index).
  • the apparatus was a two-compartment (15 x 20 x 15 cm high) box with one illuminated with white polyvinylchloride walls and the other darkened with black polyvinylchloride walls and a grid floor.
  • a guillotine door separated each compartment.
  • a 60 W lamp positioned 40 cm above the apparatus lighted up the white compartment during the experiment.
  • Scrambled footshocks (0.3 mA for 3 s) could be delivered to the grid floor using a shock generator scrambler (MedAssociates, USA).
  • the guillotine door was initially closed during the training session. Each mouse was placed into the white compartment. After 5 s, the door was raised.
  • the step-through latency that is, the latency spent to enter the darkened compartment, and the number of vocalizations were recorded.
  • the retention test was carried out 24 h after training. Each mouse was placed again into the white compartment. After 5 s, the door was raised. The step-through latency was recorded up to 300 s.
  • Alzheimer disease with spastic paraparesis neuropathological phenotype. J. Neuropathol. Exp. Neurol. 60, 483-92.

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Abstract

La présente invention concerne des combinaisons et des méthodes pour le traitement de troubles neurologiques liés à la toxicité de la protéine bêta-amyloïde et/ou à la mort neuronale. Plus spécifiquement, la présente invention concerne de nouvelles thérapies combinées contre la maladie d'Alzheimer, les troubles associés à la maladie d'Alzheimer, la maladie de Parkinson, la démence à corps de Lewy, l'atrophie multisystématisée et d'autres synucléinopathies associées, la chorée de Huntington, les neuropathies périphériques, l'alcoolisme ou le sevrage alcoolique, les manifestations neurologiques de la toxicomanie ou du sevrage des toxicomanes, la sclérose latérale amyotrophique, la sclérose en plaques, une lésion de la moelle épinière, l'épilepsie, une lésion cérébrale traumatique ou les événements ischémiques cérébraux, utilisant la 3-phénylsulfonyl-5-(pipérazin-l-yl)quinolone et le baclofène et/ou l'acamprosate.
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