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WO2015060746A1 - Combinaison pour traiter et/ou prévenir l'apparition de troubles psychiques, cognitifs, comportementaux et neurologiques lors de maladies organiques du système nerveux central de genèse diverse - Google Patents

Combinaison pour traiter et/ou prévenir l'apparition de troubles psychiques, cognitifs, comportementaux et neurologiques lors de maladies organiques du système nerveux central de genèse diverse Download PDF

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Publication number
WO2015060746A1
WO2015060746A1 PCT/RU2014/000362 RU2014000362W WO2015060746A1 WO 2015060746 A1 WO2015060746 A1 WO 2015060746A1 RU 2014000362 W RU2014000362 W RU 2014000362W WO 2015060746 A1 WO2015060746 A1 WO 2015060746A1
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memantine
melatonin
manifestations
amyloid
cognitive
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Russian (ru)
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Аллан Герович БЕНИАШВИЛИ
Максим Эдуардович ЗАПОЛЬСКИЙ
Маргарита Алексеевна МОРОЗОВА
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Valenta Intellect LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention relates to the field of pharmacology and practical medicine, namely to the combined use of drugs with a neurotropic effect, facilitating the manifestation of mental, behavioral, cognitive disorders in organic damage to the central nervous system of various origins, as well as with manifestations of amyloid intoxication.
  • the share of the psycho-organic syndrome which does not reach the degree of dementia, of vascular origin, accounts for 25% of the diagnosed cases of mental pathology in people older than 60 who have turned to a general clinic [Mikhailova N. M., 1996].
  • psycho-organic disorders with torpid phenomena, delayed psychomotor reactions, mild dysmnesthetic disorders, attention disorders can largely be determined and meet the criteria for “mild cognitive impairment” (ICD-10, heading F06.7 “Mild cognitive impairment”).
  • somatic pathology not only have a direct biological effect on the mental state, but also include a powerful psycho-traumatic factor, since they are regarded by patients as a threat to their physical health and life itself (Krylov V.I. et al., 1985; Neznanov N.G. , 1985; Gnezdilov A.V., 2002, and others).
  • the main clinical manifestation of the psycho-organic syndrome along with a disorder of memory, attention, asthenia, is a specific disorder of the sleep-wake cycle, with a decrease in the level of wakefulness during the day and a disturbance in night sleep.
  • a rhythm disorder is a factor both independently impairing the functioning of the patient, and exacerbating other symptoms of the disease.
  • Chronic traumatic encephalopathy is in many ways similar to other neurodegenerative diseases, such as Alzheimer's disease, in particular with regard to the metabolism and aggregation of tau, amyloid beta and TDP-43 (TAR-DNA binding protein) [Neuron. 2012 Dec 6; 76 (5): 886-99. doi: 10.1016 / j.neuron.2012.11.021.
  • the neuropathology and neurobiology of traumatic brain injury are in many ways similar to other neurodegenerative diseases, such as Alzheimer's disease, in particular with regard to the metabolism and aggregation of tau, amyloid beta and TDP-43 (TAR-DNA binding protein) [Neuron. 2012 Dec 6; 76 (5): 886-99. doi: 10.1016 / j.neuron.2012.11.021. The neuropathology and neurobiology of traumatic brain injury.
  • cyclooxygenase-1 in beta-amyloid-induced neuroinflammation was also studied, and attempts were made to use COX inhibitors (cyclooxygenase) as protectors for the development of Alzheimer's disease (A role for cyclooxygenase-1 in beta-amyloid-induced neuroinflammation, Eduardo Candelario-Jalario-Jalario-Jalario-Jalario Vol 1, No. 4, pp 350-353).
  • NMDA receptor antagonists In neurodegenerative processes, as well as in cerebral ischemia, an important pathogenetic role is played by hyperactivation of the glutaminergic system. Therefore, the researchers suggested the use of NMDA receptor antagonists to treat mild cognitive impairment.
  • EA 007632 The combination of NMDA antagonist and acetylcholinesterase inhibitors for the treatment of Alzheimer's disease
  • EA 008863 Combination therapy using derivatives of 1-aminocyclohexane and acetylcholinesterase inhibitors
  • EA 009668 IFN-beta alone or in combination with other drugs for the treatment of Alzheimer's disease and disorders associated with dementia
  • EA 010430 The combination of an NMDA receptor antagonist and a selective serotonin reuptake inhibitor for the treatment of depression and other mental disorders.
  • these combinations are effective in specific CNS pathologies.
  • Memantine is a voltage-dependent, medium affinity, non-competitive antagonist of NMDA receptors. Memantine blocks the effects of pathologically elevated levels of glutamate, which can lead to neuronal dysfunction. It has a neuroprotective, antispastic, antiparkinsonian effect. It inhibits glutamatergic neurotransmission and the progression of neurodegenerative processes, has a neuromodulating effect. It contributes to the normalization of mental activity, improves memory, increases the ability to concentrate, correct motor disorders [Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Arzneistoff-Forschung. 1991; 41: 773-80.]. In addition to the main mechanism of action (effect on glutamatergic transmission), memantine has an additional serotonergic effect
  • the second aspect of the therapeutic activity of memantine is a neuroprotective effect.
  • This effect is a direct result of blockade of NMDA receptors, closure of ionotrophic channels and, accordingly, stabilization of the cell membrane, which protects cells from death.
  • the neuroprotective effect of memantine has been proven in a model of cerebral ischemia in an experiment [Danysz W, Parsons CG, Mobius HJ etal. NeurotoxRes 2000; 2: 85-97.].
  • the preventive administration of memantine reduced the area of ischemic penumbra, the severity of cerebral edema, and also reduced the area of the focus of ischemia. A similar result was obtained on other models of brain damage.
  • memantine can have a stimulating effect on the synthesis of a number of neurotrophic factors, in particular, brain-specific neurotrophic factor (brain-derived neurotrophic factor), which also leads to stabilization of the neuronal membrane and protect the cell from death.
  • brain-specific neurotrophic factor brain-derived neurotrophic factor
  • NMDA receptor antagonists have a positive effect on the cognitive functions of patients with Parkinson’s disease [Damulin I.V. Rus honey. journal 2001; 9 (25): 1178-82., Litvinenko I.V., Odinak M.M. Zhurn. nevrol. and psychiatrist them. S.S. Korsakova. 2004; 4: 76-81.].
  • Memantine (1-amino-3,5-dimethyl adamantane) is an analogue of 1-amino-cyclohexane.
  • the formula is disclosed, for example, in US patents NN 4,122, 193; 4.273, 774; 5,061, 703.
  • Memantine and other 1-aminoalkylcyclohexanes have been shown to be useful in reducing various progressive neurodegenerative disorders, such as dementia in patients with moderate to severe Alzheimer's disease, Parkinson's disease, and muscle spasticity as disclosed in US Pat. Nos. 5,061,703; 5.614, 560 and 6.034, 134.
  • memantine as a neuroprotective agent for amyloid intoxication is also known (Hidalgo JJM, Alvarez XA, Cacabelos R, Quack G. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid (1-40). Brain Research, 2002, v.958, 210- 221).
  • Melatonin N-acetyl-5-methoxytryptamine
  • circadian circadian
  • NMDA M-methyl-E-aspartate
  • Melatonin protects neurons from NO aggression, an excess of which can potentiate glutamate neurotoxicity [Guerrero JM, ReiterRJ., OrtizG. etal. Melatonin prevents increases in neuronal nitric oxide and cyclic GMP production after transient brain ischemia and reperfusion in the Mangolian gerbil // J. Pineal Res. - 1997. - V.23. - p.24-31.]. Melatonin also normalizes mitochondrial activity [El-Abhar HS, Shaalan M., Barakat M. et al. Effect of melatonin and nifedipine on some antioxidant enzymes and different energy fuels in the blood and brain of global ischemic rats // J.
  • the combination may be presented in the form of a tablet, including sublingual forms, capsules, modified-release dosage forms, injection forms, suppositories, powder for the preparation of a drink, drops, including drops in the nose, transdermal, buccal, aerosol form.
  • Pharmaceutically acceptable excipients are selected to ensure the delivery of a therapeutically effective single dose amount of Memantine and Melatonin in a unit dosage form and to optimize the cost, ease and stability of the manufacturing process.
  • a prerequisite for excipients is inertness, chemical and physical compatibility with Memantine and Melatonin.
  • Excipients used in solid dosage forms, such as tablets and capsules may further include colorants and pigments, taste masking agents, flavors, sweeteners and adsorbents.
  • Gelatinized starch may be a preferred, but not exclusive, disintegrant.
  • Another preferred disintegrant is sodium carboxymethyl cellulose.
  • Binders are used as auxiliary pharmaceutically acceptable substances for wet granulation to increase the concentration of therapeutically active substances and other auxiliary ingredients in the forming granules. A binder is added to improve the fluidity of the powder and to improve compression. Binders include cellulose derivatives such as microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
  • the composition of Memantine with Melatonin is mixed with various auxiliary products to obtain a solid form of Memantine with Melatonin.
  • An additional aspect of the present invention includes a method for the preparation of the claimed composition. This method involves obtaining a solid dosage form of the claimed composition, preferably by wet mixing of the active ingredients and excipients with water, and with further drying and grinding of the granular mixture.
  • the active principle is about 40.0% by weight of the composition
  • lactose monohydrate is about 28.7%
  • microcrystalline cellulose is about 10.4%
  • starch is about 10.9%
  • carboxymethyl cellulose is about 4.0 %
  • polyvinylpyrrolidone is about 5.2%
  • magnesium stearate is about 0.8%.
  • Memantine and Melatonin comprise from about 70-80% by weight of the composition.
  • the composition comprises a diluent, such as lactose monohydrate, preferably from about 3-20% by weight of the composition; a disintegrant, such as, for example, cross-linked sodium carboxymethyl cellulose, preferably from about 2-10% by weight of the composition; a binder such as, for example, polyvinylpyrrolidone, preferably from about 2-10% by weight of the composition; and a lubricant, such as magnesium stearate, preferably from about 0.2 to 2.0% by weight of the composition.
  • a diluent such as lactose monohydrate, preferably from about 3-20% by weight of the composition
  • a disintegrant such as, for example, cross-linked sodium carboxymethyl cellulose, preferably from about 2-10% by weight of the composition
  • a binder such as, for example, polyvinylpyrrolidone, preferably from about 2-10% by weight of the composition
  • the implementation of Memantine and Melatonium is from about 90% by weight of the composition.
  • the composition comprises a diluent, such as lactose monohydrate, in the range of 3-10% by weight of the composition; a disintegrant, for example, carboxymethyl cellulose, preferably from about 2-5% by weight of the composition; a binder, such as polyvinylpyrrolidone, preferably from about 2-5% by weight of the composition; and a lubricant, for example magnesium stearate, preferably from about 0.2-2.0% by weight of the composition.
  • a diluent such as lactose monohydrate
  • a disintegrant for example, carboxymethyl cellulose, preferably from about 2-5% by weight of the composition
  • a binder such as polyvinylpyrrolidone
  • a lubricant for example magnesium stearate, preferably from about 0.2-2.0% by weight of the composition.
  • Memantine with Melatonin comprises from about 60 to 90% or 70-80%) of the composition.
  • these compositions comprise one or more of starches, such as corn starch, lactose monohydrate, microcrystalline cellulose, gelatinized starch, carboxymethyl cellulose; sodium salt of carboxymethyl starch ether; polyvinylpyrrolidone; hydroxypropyl methylcellulose; magnesium stearate; and a mineral salt such as talc.
  • these compositions comprise lactose monohydrate, corn starch, sodium carboxymethyl cellulose, polyvinylpyrrolidone, talc and magnesium stearate.
  • FIG. 1 shows the design of the experiments in Example 1 on the study of substances for functional and morphological disorders caused by the introduction of the beta-amyloid peptide into the lateral ventricle of the mouse brain.
  • FIG. 3 depicts a representative black and white micrograph of a superimage of a section of a brain passing through the dorsal hippocampus.
  • the arrow indicates the route of administration of the beta-amyloid peptide. Rectangles indicate CA1, SAZ of the hippocampus and the area of the sensory-motor cortex.
  • FIG. 4 depicts the effect of test substances on memory impairment in mice caused by amyloid beta in a new object recognition test. Presents the average values of the preference index of the new object.
  • FIG. 5 depicts representative black and white micrographs of the CA1 hippocampus region in control (A) and after administration of amyloid beta into the lateral ventricle of the brain (B).
  • Micrographs B and D show the effect of the combination of memantine 5 mg / kg + melatonin 3 mg / kg (B), memantine 10 mg / kg + melatonin 6 mg / kg (G) on neurodegeneration caused by the introduction of beta-amyloid.
  • Microphotographs were taken at x200 magnification.
  • the arrow shows pycnotic cells stained with hematoxylin-eosin.
  • FIG. 6 depicts representative black and white micrographs of the SAZ hippocampus region in control (A) and after administration of amyloid beta into the lateral ventricle of the brain (B).
  • Micrographs B and D show the effect of the combination of memantine 5 mg / kg + melatonin 3 mg / kg (B), memantine 10 mg / kg + melatonin 6 mg / kg (G) on neurodegeneration caused by the introduction of beta-amyloid.
  • Microphotographs were taken at x200 magnification.
  • the arrow shows pycnotic cells stained with hematoxylin-eosin.
  • FIG. 7 shows representative black and white microphotographs of the sensory motor region of the cortex mouse brain in control (A) and after the introduction of beta-amyloid into the lateral ventricle of the brain (B.
  • Micrographs B and D show the effect of the combination of memantine 5 mg / kg + melatonin 3 mg / kg (B), memantine 10 mg / kg + melatonin 6 mg / kg (G) for neurodegeneration caused by the introduction of beta-amyloid.
  • Microphotographs were taken at a magnification of x200.
  • the arrow shows pycnotic cells stained with hematoxylin-eosin.
  • mice All experiments were performed on male mice of the C57BL / 6 line. Animals were purchased from Harlan (England). The average age of the animals at the time of arrival at the vivarium of the Biomedical Center of the University of Tartu was 5.5 (40 mice) and 6 weeks (20 mice). Upon arrival, animals were quarantined for 2 weeks at the vivarium of the Biomedical Center of the University of Tartu. After which the animals were transferred to the vivarium of the Institute of Pharmacology (room number 3028). Animals were kept in plastic cages (5 mice per cage) measuring 25 cm x 45 cm x 12 cm (WxDxH) without restriction in food and water with a 12-hour light cycle (the light turns on automatically at 8.00).
  • Table 1 shows the scheme of administration of substances.
  • the first administration of the test substances was carried out 24 hours after the injection of amyloid beta into the lateral ventricle of the mouse brain. Substances were administered within 8 days (once a day), at the same time from 9.00 to 11.00 hours. All solutions the test substances were prepared every day immediately before administration and after their preparation were encoded by the leader and transmitted in encoded form to the experimenter. On the 6th and 7th day of the introduction of the test substances with animals, behavioral experiments were carried out (see Figure 1).
  • memantine HCL 5 mg was dissolved in 9 ml of water. Separately, 3 mg of melatonin was weighed, placed in a mortar and 2 drops of Tween-80 emulsifier were added, triturated until a homogeneous mass was formed, adding 1 ml of water in portions. The resulting emulsion was mixed with a solution of memantine (9 ml). Before administration, the emulsion was vigorously shaken on a shaker. The resulting emulsion was administered in a volume of 0.1 ml per 10 g of mouse body weight, which corresponds to doses of memantine 5 mg / kg and melatonin 3 mg / kg.
  • Solutions 1-5 were introduced into the stomach using a metal probe for mice (FTSS-20S-38) from Salomon Scientific (USA).
  • peptide substance 1 mg was dissolved in 1 ml of sterile water and placed in a sterile incubator at a temperature 37 ° C for 96 hours for peptide aggregation (oligomeric form). Immediately before use, the solution was diluted with sterile water to a peptide concentration of 16 nM and introduced into the left lateral ventricle of the mouse brain in the amount of 48 picograms in a volume of 3 microliters.
  • beta-amyloid peptide The introduction of the beta-amyloid peptide into the lateral ventricle of the mouse brain.
  • amyloid beta into the lateral ventricle of the mouse brain was performed under general anesthesia.
  • a mixture of hypnorm (Hypnorm, VetaPharma; Lot P736 / 001; contains 0.315 mg of fentanyl and 10 mg of fluanisone in 1 ml), dormicum (Dormicum, Roche; Lot: F1038F71, 5 mg / ml) and water in a ratio of 1: 1 was used : 2.
  • the mixture was administered ip in a volume of 0.1 ml per 10 g of body weight.
  • the coordinates for introducing amyloid beta into the lateral ventricle were found using a Computer-assisted Stereotaxic system using the parameters of the mouse brain atlas (The Mouse Brain, in Stereotaxic Coordinates, KBJ Franklin and G. Paxinos, 2012).
  • the coordinates for the introduction of amyloid beta with respect to Bregma were as follows: forward - 0.5 mm, laterally - 1 mm, ventrally - 2 mm.
  • a solution of the substance was injected at a speed of 0.75 ⁇ l / min and after the end of the infusion, the needle remained in the brain for 1 min.
  • the control group received an infusion of sterile water in a volume of 3 ⁇ l. After this, the wound was treated with an antiseptic solution, sutured and animals were placed on a heated table until the anesthesia was completely exited.
  • mice Surgical operation caused the death of four mice, one animal in groups intended for the introduction of the studied substances.
  • the animal groups to which memantine or memantine + melatonin was to be administered consisted of 9 mice.
  • a recognition test of a new object was used. This test is widely used. to assess episodic memory in animals and its violation is characteristic of Alzheimer's patients. The test is based on the fact that healthy animals examine a new object much more time than the old one.
  • the experience consisted of three phases: the addictive phase, the training phase and the retention phase.
  • mice were individually placed in a wooden box measuring 50 cm x 50 cm x 50 cm (length x width x height), located in an experimental room dimly lit by incandescent lamps, with a constant light of 60 lux.
  • the box floor was divided into 16 identical squares with a side length of 12.5 cm.
  • the animal was in the box for 5 minutes and the experimenter recorded the number of crossed squares. This indicator, in the future, was used to assess the motor activity of mice. After 5 minutes, the animal was removed from the box and the floor of the box was rubbed with a 5% ethanol solution to eliminate odor.
  • the training phase was conducted. For this, the animal was again placed in the center of the box on the floor of which two identical objects were installed. The objects were two wooden cubes located in opposite corners of the box (Fig. 2). The animal was given the opportunity to examine objects for 5 minutes, and at the same time, the time during which the animal examined each of the objects was recorded. These data are necessary to assess the degree of motivation and research activity of animals. After each animal, the box floor was wiped with a 5% ethanol solution. At the end of the experiment, the animal was placed in a home cage. 3) Retention phase
  • test substances were administered to the mice (seventh injection) and 1 hour after the administration of the substances, the animals were again placed in the study box, in which one object was replaced with a new object of a different shape and color (Fig. 3) .
  • the research preference coefficient of a new object was presented as the ratio of the time of research of a new object in relation to the total time of research of the old and new objects according to the formula (Tnov x100) / (Tst + Tnov), where Tst and Tnov are the time of investigation of the old and new objects.
  • Sagittal sections of the brain (40 ⁇ m thick) passing through the dorsal hippocampus were prepared using a vibrating microtome (Leica, Germany). Slices were placed on plates (one slice per well) filled with 0.1 M phosphate buffer and stored at 4 ° C (shelf life 3-4 days). For each animal, 4 sections were selected passing through the dorsal hippocampus. For this, all slices from each animal were distributed into a series of 6 slices each. For each animal, the selection of sections was carried out based on the Cavalieri principle: first, a section was randomly selected from the first series and then from each subsequent series was taken slice with the same serial number.
  • Staining was performed on free-floating sections in a 24-seater plate. Sections were washed in 0.1 M phosphate buffer, then incubated in a solution of 0.025% trypsin (Sigma, USA) and 0.1% CaC in phosphate buffer for 10 min. After washing the sections in phosphate buffer, 0.25% Triton x-100 solution (Sigma, USA) was added to them and the sections were incubated for 1 hour.
  • pycnotic cells were analyzed and counted in the structures CA1 and CAS of the hippocampus and sensorimotor region of the cortex. Pycnotic cells were defined as cells containing condensed hyperchromic nuclei, nuclear fragments, and condensed cytoplasm. Counting was carried out in each square, as shown in FIG. 5, 6, 7. The square area was set by the NewCast program and, depending on the size of the structure and cell density, it varied in the range of 0.1-0.5 mm 2 .
  • the number of pycnotic cells and the area on which they were determined on four selected sections were summed up and the average density of pycnotic cells per 1 mm 2 section was calculated and calculated.
  • the obtained mean densities of pycnotic cells in the CA1, SAH areas of the hippocampus and the sensorimotor region of the cortex for each animal were subsequently used for statistical analysis.
  • mice For each group of mice, the mean values (M) were calculated ⁇ the standard error of the mean (t). Further, the data were analyzed using the Student's ⁇ -test (control and beta-amyloid), one-way analysis of variance, followed by the retrospective Bonferroni criterion (action of the studied substances, dose effect). In a comparative assessment of the action of combinations of substances, two-way analysis of variance was used. Differences between groups were considered significant at p ⁇ 0.05. Statistical data processing was performed using statistical software GraphPad PRISM-5 (USA).
  • a therapeutic daily dose of memantine of 20 mg / day provides a plasma concentration level of 0.5-1 ⁇ mol / liter of plasma (12).
  • memantine concentrations (1 ⁇ mol / liter of plasma) were observed after administration of memantine at a dose of 30 mg / kg / day (9). Since the aim of the study was to analyze whether melatonin can enhance the action of memantine, in the study, memantine was used in doses lower than those that give the maximum therapeutic plasma concentrations. In this study, doses of memantine 5 and 10 mg / kg were used, and, accordingly, the concentrations of memantine in these doses should be lower than the maximum therapeutic (1 ⁇ mol / liter of plasma).
  • mice have reverse rhythms, and their sleep phase coincides with daytime, the calming effect of the memantine + melatonin combination on hyperactivity of mice in the daytime indicates the restoration of normal circadian rhythms, which may have therapeutic value in patients with Alzheimer's disease.
  • mice of the control group showed a pronounced preference in the study of a new object: the index of preference in the control group was 87.8 D2.3%. 7 days after the injection of beta amyloid into the lateral ventricle of the brain in mice, a decrease in the preference index of the new object to 49.7 P 14% was observed. Statistical analysis showed a highly reliable (p ⁇ 0.0001, Student t-test) difference compared with the control group. A decrease in the preference index indicates memory impairment in mice after administration of beta-amyloid. Memantine and memantine in combination with melatonin increased the preference index, which indicates an improvement in memory impaired by the introduction of beta-amyloid.
  • the next step in the statistical analysis was to compare whether the combination of memantine + melatonin is different from the action of memantine in terms of anti-amnestic effect.
  • two-way analysis of variance was used, where one factor was “substance” and another factor was “dose” (Table 4).
  • Table 4 shows the average values of the index of preference for a new object ⁇ standard errors of the mean per group of 9 animals.
  • the effect of the melatonin + memantine combination on neuronal death caused by the administration of amyloid beta in the CA1 region is shown in FIG. 5.
  • the results of statistical analysis are shown in Table 5.
  • the active substances Melatonin 3 mg / Memantine 10 mg were taken; Melatonin 5 mg / Memantine 20 mg;
  • the passive avoidance reaction test is the main model for assessing the effect of substances on the formation and reproduction of short-term memory in normal and in the conditions of its violation, artificial amnesia. And passive avoidance reaction is the most informative of the methods used today to assess the effectiveness of substances with the effect on the central nervous system of mammals ("Guide to experimental (preclinical) study of new pharmacological substances ”, 2000).
  • the passive avoidance reaction (conditioned reflex of passive avoidance in a dark, light chamber) in mice was performed on the basis of electrodermal reinforcement according to the method of Cumin et al. (1982) taking into account the recommendations of Mondadori et al. (1990).
  • the mouse installation of Lafayette Instrument Co., USA was a black chamber with an electrode floor and a white plastic platform, which was placed on the floor in the center of the chamber. Mice, one at a time, were placed on a plastic platform. Animals descend / jump from the platform onto the electrode floor, where they receive an electric shock, the so-called punishment. Electric current was supplied, the field as the animal rested with all four paws. The natural reaction of the animal is to return to a dead or safe platform. After several minutes of training, on average about 5 minutes, passive avoidance reaction was developed in mice and they remained on a safe platform. Tests for memorizing passive avoidance reaction were carried out at successive intervals after an amnesic effect.
  • test substances and isotonic sodium chloride solution were carried out in comparison with Melatonin 5 mg (monopoly) and Memantine 10 mg (monopoly), in accordance with the above the formula for adapting to animal models in / b the introduction to the training of mice, once a day, for 5 days.
  • the combination can be indicated in medical conditions that are accompanied by clinical manifestations of organic psychosyndrome (and its most significant component - dementia): Alzheimer's disease, vascular (multi-infarction) dementia, alcoholism, intracranial volume processes - tumors, subdural hematomas and brain abscesses, anoxia, cranial brain injury, normotensive hydrocephalus, Parkinson's disease, Huntington's chorea, progressive supranuclear palsy, Peak's disease, amyotrophic lateral sclera h, spinocerebellar degeneration, ophthalmoplegia in combination with metachromatic leukodystrophy (adult form), Gellerwarden-Spatz disease, hash psychosis, advanced stages, infections, Creutzfeldt-Jakob disease, viral encephalitis, progressive multifocal leukocytic leukemic leukemia, meningitis; Deficit states, Gaye-Wernicke-Korsakov

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Abstract

L'invention se rapporte au domaine de la pharmacologie et de la médecine pratique, et concerne l'utilisation combinée de préparations médicamenteuses ayant une action neurotrope soulageant l'apparition de troubles psychiques, comportementaux et cognitifs lors d'une affection organique du système nerveux central de genèse diverse, ainsi que lors d'une intoxication amyloïde. Cette composition pharmaceutique contient de la mélatonine et de la mémantine dans des quantités thérapeutiquement efficaces.
PCT/RU2014/000362 2013-10-21 2014-05-21 Combinaison pour traiter et/ou prévenir l'apparition de troubles psychiques, cognitifs, comportementaux et neurologiques lors de maladies organiques du système nerveux central de genèse diverse Ceased WO2015060746A1 (fr)

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RU2013146812/15A RU2536270C1 (ru) 2013-10-21 2013-10-21 Комбинация для коррекции неврологического и психоэмоционального статуса при органических нарушениях цнс
RU2013146812 2013-10-21

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018004391A1 (fr) * 2016-06-29 2018-01-04 Общество С Ограниченной Ответственностью "Валента-Интеллект" Composition pharmaceutique contenant une combinaison de mémantine et de mélatonine
RU2654713C1 (ru) * 2016-06-29 2018-05-22 Общество С Ограниченной Ответственностью "Валента-Интеллект" Фармацевтическая композиция, содержащая комбинацию мемантина и мелатонина

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2623865C1 (ru) * 2016-06-29 2017-06-29 Общество С Ограниченной Ответственностью "Валента-Интеллект" Фармацевтическая композиция, содержащая комбинацию мемантина и мелатонина

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130116215A1 (en) * 2011-10-28 2013-05-09 Mireia Coma Combination therapies for treating neurological disorders
RU2488388C1 (ru) * 2012-05-24 2013-07-27 Ооо "Валента Интеллект" Фармацевтическая композиция для профилактики и лечения психических, поведенческих, когнитивных расстройств

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050031651A1 (en) * 2002-12-24 2005-02-10 Francine Gervais Therapeutic formulations for the treatment of beta-amyloid related diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130116215A1 (en) * 2011-10-28 2013-05-09 Mireia Coma Combination therapies for treating neurological disorders
RU2488388C1 (ru) * 2012-05-24 2013-07-27 Ооо "Валента Интеллект" Фармацевтическая композиция для профилактики и лечения психических, поведенческих, когнитивных расстройств

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018004391A1 (fr) * 2016-06-29 2018-01-04 Общество С Ограниченной Ответственностью "Валента-Интеллект" Composition pharmaceutique contenant une combinaison de mémantine et de mélatonine
RU2654713C1 (ru) * 2016-06-29 2018-05-22 Общество С Ограниченной Ответственностью "Валента-Интеллект" Фармацевтическая композиция, содержащая комбинацию мемантина и мелатонина
KR20190025647A (ko) * 2016-06-29 2019-03-11 엘티디 "발렌타-인텔렉트" 메만틴 및 멜라토닌의 배합물을 함유하는 약제학적 조성물
AU2017288035B2 (en) * 2016-06-29 2020-12-03 Ltd "Valenta-Intellekt" Pharmaceutical composition containing combination of memantine and melatonin
KR102280457B1 (ko) 2016-06-29 2021-07-23 엘티디 "발렌타-인텔렉트" 메만틴 및 멜라토닌의 배합물을 함유하는 약제학적 조성물
IL263976B1 (en) * 2016-06-29 2023-05-01 Valenta Intellekt Ltd Preparations containing memantin and melatonin
IL263976B2 (en) * 2016-06-29 2023-09-01 Valenta Intellekt Ltd Preparations containing memantin and melatonin

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