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(12) Patent Application Publication (10) Pub. No.: US 2016/0354335 A1 COHEN Et Al US 20160354335A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0354335 A1 COHEN et al. (43) Pub. Date: Dec. 8, 2016 (54) COMBINATION OF BACLOFEN, Publication Classification ACAMPROSATE AND MEDIUM CHAN TRGLYCERDES FOR THE TREATMENT (51) Int. Cl. OF NEUROLOGICAL DISORDERS A6II 3L/23 (2006.01) A6II 3/85 (2006.01) (71) Applicant: PHARNEXT, Issy Les Moulineaux A636/85 (2006.01) (FR) A 6LX 3L/97 (2006.01) (52) U.S. Cl. (72) Inventors: DANIEL COHEN, SAINT CLOUD CPC ............. A6 IK3I/23 (2013.01); A61K 31/197 (FR), ILYA CHUMAKOV, (2013.01); A61K 31/185 (2013.01); A61 K VAUX-LE-PENIL (FR), SERGUEI 36/185 (2013.01) NABIROCHKIN, CHATENAY-MALABRY (FR): (57) ABSTRACT RODOLPHE HAJJ, SAINT The present invention relates to combinations and methods GERMAIN EN LAYE (FR) for the treatment of neurological disorders related Amyloid (21) Appl. No.: 15/117,774 beta toxicity and/or neuronal death and/or glucose impaired neuronal metabolism. More specifically, the present inven (22) PCT Fed: Feb. 10, 2015 tion relates to novel combinatorial therapies of Alzheimer's disease, Alzheimer's disease related disorders, frontotempo (86) PCT No.: PCT/EP2015/052694 ral dementia, Parkinson's disease, Lewy body dementia, Huntington's disease, peripheral neuropathies, alcoholism S 371 (c)(1), or alcohol withdrawal, neurological manifestations of drug (2) Date: Aug. 10, 2016 abuse or drug abuse withdrawal, amyotrophic lateral scle rosis, multiple Sclerosis, spinal cord injury, epilepsy, trau Related U.S. Application Data matic brain injury or brain ischemic events based on (60) Provisional application No. 61/938,340, filed on Feb. baclofen, acamprosate and at least one medium chain tri 11, 2014. glyceride. Patent Application Publication Dec. 8, 2016 Sheet 1 of 2 US 2016/0354335 A1 S. 70 S t 6. --- -- -- r is 505 ... .- & Scr AB vehicle ST is 8 Sw 0.555 g/kgid 166 g/kg/d 5 g/kg/d . S i 60 50 40 Ser AB waits S. A 480 g/kg bid 32 g/kg bid C SO S 70 (5. - X------------------------- 50 s Ser AB vehicle SC 3C BCL A A 3 A 3. 3S 55 C3 is Figure 1 Patent Application Publication Dec. 8, 2016 Sheet 2 of 2 US 2016/0354335 A1 A 350 - a 300 - g 250 --- 200 - E 150 - e 100 50 s Scr Af vehicle CSMC (555 CSMCT 1.66 CSMCT 5 0.555 g/kg/d 66 g/kg/d 5 g/kg.'d B 350 a 25050 l :- 200 5. E 150 - 50 d. i. Scr AB vehicle EC 38 AP is 480 g/kg bid 32 g/kg bid 35 - C veice 3. A A 3 3 S3 3C S. Figure 2 US 2016/0354335 A1 Dec. 8, 2016 COMBINATION OF BACLOFEN, tive process is a series of events triggered by the abnormal ACAMPROSATE AND MEDIUM CHAIN processing of the Amyloid Precursor Protein (APP) 12. TRGLYCERDES FOR THE TREATMENT and the “neuronal cytoskeletal degeneration hypothesis' OF NEUROLOGICAL DISORDERS 13, which proposes that cytoskeletal changes are the triggering events. The most widely accepted theory explain FIELD OF THE INVENTION ing AD progression remains the amyloid cascade hypothesis 14-16 and AD researchers have mainly focused on deter 0001. The present invention relates to new combinations mining the mechanisms underlying the toxicity associated and methods for the treatment of neurological diseases and with Abeta proteins. Microvascular permeability and remod disorders. More specifically, the present invention relates to eling, aberrant angiogenesis and blood brain barrier break novel combinatorial therapies of neurological disorders, down have been identified as key events contributing to the based on baclofen, acamprosate and medium chain mono-, APP toxicity in the amyloid cascade 17. On the contrary, di- or tri-glyceride(s) combinations. Tau protein has received much less attention from the pharmaceutical industry than amyloid, because of both BACKGROUND OF THE INVENTION fundamental and practical concerns. Moreover, synaptic 0002 Alzheimer's disease (AD) is the prototypic cortical density change is the pathological lesion that best correlates dementia characterized by memory deficit together with with cognitive impairment than the two others. Studies have dysphasia (language disorder in which there is an impair revealed that the amyloid pathology appears to progress in ment of speech and of comprehension of speech), dyspraxia a neurotransmitter-specific manner where the cholinergic (disability to coordinate and perform certain purposeful terminals appear most Vulnerable, followed by the gluta movements and gestures in the absence of motor or sensory matergic terminals and finally by the GABAergic terminals impairments) and agnosia (ability to recognize objects, 11. Glutamate is the most abundant excitatory neurotrans persons, Sounds, shapes, or Smells) attributable to involve mitter in the mammalian nervous system. Under pathologi ment of the cortical association areas. Special symptoms cal conditions, its abnormal accumulation in the synaptic Such as spastic paraparesis (weakness affecting the lower cleft leads to glutamate receptors overactivation 18, that extremities) can also be involved 1-4. results in pathological processes and finally in neuronal cell 0003 Incidence of AD increases dramatically with the death. This process, named excitoxicity, is commonly age. AD is at present the most common cause of dementia. observed in neuronal tissues during acute and chronic neu It is clinically characterized by a global decline of cognitive rological disorders. function that progresses slowly and leaves end-stage patients 0007 Another principal functional hallmark of AD is bound to bed, incontinent and dependent on custodial care. profound generalized decline of energy metabolism charac Death occurs, on average, 9 years after diagnosis 5. United terized by mitochondrial dysfunction and development of Nation population projections estimate that the number of insulin resistance State, leading to reduced glucose uptake people older than 80 years will approach 370 million by the and, finally, synapse collapsing. An impaired brain metabo year 2050. Currently, it is estimated that 50% of people older lism is often suggested as a major etiological cause of than age 85 years are afflicted with AD. Therefore, more cognitive decline in age related dementias 28.29 and, in the than 100 million people worldwide will suffer from demen case of AD, might precede, accompany or even provoke tia in 50 years. The vast number of people requiring constant Abeta plaques deposition which, in a vicious circle mecha care and other services will severely affect medical, mon nism, could further inhibit glucose uptake 30. etary and human resources 6. 0008 Up to know, two kinds of medication, accounting 0004 Memory impairment is the early feature of the for only five drugs approved in most countries, are used for disease and involves episodic memory (memory for day improving or slowing down symptoms of AD which lay on today events). Semantic memory (memory for Verbal and Some acetylcholinesterase modulators and a blocker of visual meanings) is involved later in the disease. By con NMDA glutamate Receptors (NMDAR) 19-21). trast, working memory (short-term memory involving struc 0009 Acetylcholinesterase inhibitors such as donepezil, tures and processes used for temporarily storing and rivastigmine, tacrine and galantamine are currently available manipulating information) and procedural memory (uncon in the market and are efficient in symptomatic relief with scious memory that is long-term memory of skills and beneficial effects on cognitive, functional and behavioral procedure) are preserved until late. As the disease pro symptoms (in Aliabadi 22). gresses, the additional features of language impairment, 0010 NMDAR antagonists that target various sites of visual perceptual and spatial deficits, agnosias and apraxias this receptor have been tested to counteract excitoxicity. emerge. Uncompetitive NMDAR antagonists target the ion channel 0005. The classic picture of AD is sufficiently character pore thus reducing the calcium entry into postsynaptic istic to allow identification in approximately 80% of cases neurons. Only one of them, namely memantine, reached the 7. Nevertheless, clinical heterogeneity does occur which is approval status in moderate to severe AD. This molecule is important for clinical management but also provides further however of limited benefit to most AD patients, because it implication of specific medication treatments for function has only modest symptomatic effects and further has shown ally different forms 8. no significant effects in mild Alzheimer's disease 23.24. 0006. The pathological hallmark of AD includes amyloid Furthermore many other NMDAR antagonists have failed in plaques containing beta-amyloid (Abeta), neurofibrillary advanced clinical trials for several neurodegenerative dis tangles containing Tau and neuronal and synaptic dysfunc orders 20.25.26). Another approach in limiting excitoxicity tion and loss 9-11. For the last decade, two major hypoth consists in inhibiting the presynaptic release of glutamate. eses on the cause of AD have been proposed: the "amyloid O011 WO2009/133 128, WO2009/133141, WO2009/ cascade hypothesis', which states that the neurodegenera 133142, WO2011/054759, and WO2012/117076 disclose US 2016/0354335 A1 Dec. 8, 2016 drug combinations suitable for use in the treatment of AD. capric acid (C10) and/or lauric acid (C12). In this regard, WO2012/117076 particularly discloses the therapeutic effi preferred MCT for use in the invention are caproic triglyc cacy of baclofen-acamprosate combination in AD, including eride, caprylic triglyceride, capric triglyceride and lauric for the protection of glutamate toxicity and/or Abeta toxicity. triglyceride. 0012 Despite active research in this area, there is still a 0020. As it will be further disclosed in the present appli need for alternative or improved efficient therapies for cation, the compounds in the compositions or combinations neurological disorders and, in particular, neurological dis of the invention may be formulated separately or together. orders which are related to glutamate and/or Abeta toxicity Also, they may be administered simultaneously, separately, and/or impaired glucose metabolism in neuronal cells. sequentially and/or repeatedly to a subject.
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