WO2007136155A1 - Procédé et compositions à base d'érythropoïétine pour traiter les maladies des motoneurones - Google Patents

Procédé et compositions à base d'érythropoïétine pour traiter les maladies des motoneurones Download PDF

Info

Publication number
WO2007136155A1
WO2007136155A1 PCT/KR2006/005065 KR2006005065W WO2007136155A1 WO 2007136155 A1 WO2007136155 A1 WO 2007136155A1 KR 2006005065 W KR2006005065 W KR 2006005065W WO 2007136155 A1 WO2007136155 A1 WO 2007136155A1
Authority
WO
WIPO (PCT)
Prior art keywords
epo
motor neuron
composition
erythropoietin
als
Prior art date
Application number
PCT/KR2006/005065
Other languages
English (en)
Inventor
Jai Jun Choung
Seung Hyun Kim
Hee Tae Kim
Seong Ho Koh
Hyun Young Kim
Original Assignee
Corestem Co., Ltd.
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 Corestem Co., Ltd. filed Critical Corestem Co., Ltd.
Publication of WO2007136155A1 publication Critical patent/WO2007136155A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a composition for treating motor neuron diseases
  • MNDs amyotrophic lateral sclerosis
  • ALS amyotrophic lateral sclerosis
  • EPO erythropoietin
  • MNDs Motor neuron diseases
  • PLS amyotrophic lateral sclerosis
  • PMA progressive muscular atrophy
  • PBP progressive bulbar palsy
  • ALS Amyotrophic lateral sclerosis
  • MNDs motor neuron diseases
  • ALS causes, from a pathological aspect, the loss of pyramidal cells in the cerebral motor cortex (i.e., giant Betz cells), anterior spinal motor neurons and brain stem motor neurons, and degeneration thereof into pyramidal cells; while ALS shows, from a clinical aspect, both upper motor neurons (UMN) and lower motor neurons (LMN) signs, and shows rapid clinical deterioration after onset of the disease, thus leading to death within a few years.
  • UNN upper motor neurons
  • LPN lower motor neurons
  • ALS pathogenesis of ALS is still not known clearly, like the case in other various de- generative neurological lesions; however, the statistical data showing occupational relevancy suggest that the probability of incidence is increased by physical trauma, exposure to heavy metals, excessive oxidative injury, and the like.
  • EPO erythropoietin
  • erythropoietin is a glycoprotein associated with the production of erythrocytes, and it has been reported that EPO is expressed in large quantities in cerebral neurons and nervous tissues (see Marti, et al., Kidney Int., 51:416-418, 1997; and Morishita, et al., Neuroscience, 76:105-116, 1997). Furthermore, it is reported that EPO has effects of increasing the cell survival rate or protecting neurons, alone or together with other cytokines and hormones, in animal models and neural cells related to neurological diseases such as ischemic lesions, Alzheimer's disease, Parkinson's disease, Huntington's disease (see US Patent Application Publication Nos.
  • the present inventors have conducted research on a new method for treating motor neuron diseases, particularly ALS, and found that when EPO is administered to animal models as well as patients with ALS diseases, clinical deterioration is mitigated in the animal disease models and the patients with amyotrophic lateral sclerosis, and a significant therapeutic effect is obtained, thereby completing the present invention.
  • FIG. 1 is a graph showing clinical changes in a mouse model with amyotrophic lateral sclerosis (SODl mutant transgenic mouse model), after administration of EPO
  • FIG. 2 is a graph showing changes in the survival period of the mouse model with amyotrophic lateral sclerosis (SODl mutant transgenic mouse model) according to the
  • FIG. 3 is a graph showing changes in the degree of expression of COX-2 when EPO was administered to the mouse model with amyotrophic lateral sclerosis (SODl mutant transgenic mouse model).
  • Fig. 4 is a diagram illustrating the course of classifying a patient group to be administered with rhEPO and a control group.
  • Fig. 5 is a diagram illustrating the course of treatment by administering rhEPO to
  • Fig. 6 is a graph showing changes in the ALSFRS-r scores during a time period from 3 months before the injection of EPO and to 3 months after the injection of EPO to ALS patients (group A) (- ⁇ -: group A-I, - ⁇ -: group A-II, -O-: group A).
  • Fig. 7 is a graph showing differences in the ALSFRS-r scores between before and after the injection of EPO to ALS patients (group A).
  • Fig. 8 is a graph showing the effects immediately perceived by the patients after administration of EPO to ALS patients (+: positive).
  • Fig. 9 is a graph showing changes in the neurophysiological index during a period of 3 months after the first EPO administration to ALS patients.
  • the present invention relates to a composition for treating motor neuron diseases, particularly ALS, the composition comprising EPO, or an EPO fragment or an analogue thereof.
  • EPO means a substance that binds to an EPO receptor in an individual to express and then activate the EPO receptor, thereby treating and/or preventing the motor neuron diseases.
  • EPO is produced usually in the kidney of an adult or the liver of a fetus, conducts oxygen delivery to modulate erythrocyte formation, as well as to perform a function related to erythropoiesis for regulating the production of erythrocyte cells.
  • EPO performs functions related to erythropoiesis and has an ability of producing non-erythrocytes that usually contributes treatment and prevention of motor neuron diseases.
  • the forms of erythropoietin useful in the practice of the present invention encompass naturally-occurring, synthetic and recombinant forms of erythropoietin, erythropoietin analogues, erythropoietin mimetics, erythropoietin fragments, hybrid erythropoietin molecules, erythropoietin receptor-binding molecules, glycoprotein hormones which are produced from the body to regulate the production of blood cells, and the like.
  • the "EPO" as used herein can be used to refer to all of the above-listed useful forms of EPO.
  • EPO fragment refers to a polypeptide including at least a fragment for performing a physiological function by EPO.
  • the EPO fragment of the present invention binds to an EPO receptor and then expresses and activates the EPO receptor.
  • the prevention and/or treatment of motor neuron diseases are mediated by the interaction between the EPO fragment and the erythropoietin receptor.
  • These EPO fragments can have a higher EPO receptor-binding ability than the native human EPO.
  • EPO analogue refers to a polypeptide with one or more changes in the amino acid sequence which encodes EPO or an EPO fragment, which can perform various physiological functions mediated through interaction with the erythropoietin receptor.
  • the EPO analogues of the present invention can be generated by site-directed mutagenesis having additions, deletions, or substitutions of amino acid residues that alter sites available for increasing or changing the gly- cosylation sites which do not perturb the secondary or tertiary conformation required for biological activity.
  • These EPO analogues can have a higher EPO receptor-binding ability than the native human EPO.
  • EPO examples of EPO, an EPO fragment, or an analogue thereof of the present invention include various forms such as an EPO dimer, an EPO polymer, and an EPO isoform, but are not limited thereto.
  • the EPOs, EPO fragments, or analogues thereof of the present invention can be produced by cell culture; by extraction and isolation from animals including a human; by chemical synthesis or a genetically recombinant vector; or by other means.
  • the EPO of the present invention is preferably a human EPO, and more preferably a recombinant human EPO having a high physiological activity.
  • composition of the present invention can further comprise at least one other factor, in addition to EPO, an EPO fragment, or an analogue thereof.
  • Other factors refer to factors that can perform a function of delivering erythropoietin across a human endothelial cell barrier and/or of protecting cells, or the like.
  • growth factors such as FGF, EGF, IGFs, TGFs, and NGF
  • neurotrophic factors such as BNF and CTF
  • peptide radiopharmaceuticals such as BNF and CTF
  • antisense drugs antibodies to biological activators
  • immunosuppressants such as cyclosporine
  • cytokines such as in- terleukin, interferon, and LIF
  • GSK glycogen synthase kinase
  • composition of the present invention can be used in a mixture with a pharmaceutically acceptable carrier or excipient, or after being diluted with a diluent.
  • suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydrox- ybenzoate, talc, magnesium stearate and mineral oils.
  • the composition can further comprise a filler, an anti-coagulating agent, a lubricant, a humectant, a perfume, an emulsifier, an antiseptic, or the like, if desired.
  • the composition of the present invention can be administered through various administration routes including oral, topical (including buccal, sublingual, dermal, and intraocular), parenteral (including subcutaneous, intradermal, intrathecal, intraperitoneal, intramuscular, intravascular, and intraarticular), and transdermal administration, preferably parenteral administration, and more preferably intrathecal, intraperitoneal, intramuscular, and intravascular administration.
  • the parenteral administration for example, the intravenous administration, can be conducted by using a needle, or a means compatible therewith, and a pharmaceutically acceptable carrier can be contained in the composition.
  • the composition of the present invention is preferably administered through an intravenous administration route at an appropriate dosage in a liquid dosage form.
  • the oral administration of the composition of the present invention for example, can be administered in a combination of an appropriate carrier in a liquid or solid dosage form.
  • composition of the present invention, and other motor neuron disease- treating substances known in the art can be simultaneously or sequentially administered to an individual.
  • the composition comprising EPO, an EPO fragment, or an analogue thereof of the present invention can be administered at an onset stage of motor neuron diseases, or at a significantly advanced stage of motor neuron diseases.
  • it can be administered at about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours after the onset of the ALS symptom (for example, an upper motor neuron sign, a lower motor neuron sign, or a brain stem sign), but not limited thereto.
  • the composition of the present invention can be administered for prevention of motor neuron diseases.
  • Such the administration can be repeatedly conducted, if desired. For example, if clinically desired, it can be repeatedly administered daily, or every 1 to 12 weeks, preferably every 3 to 8 weeks after a predetermined time interval, but not limited thereto.
  • the composition of the present invention can be formulated in a method well- known in the art to provide a rapid or sustained release of the active ingredients after administration of the composition into an individual.
  • the composition may be formulated into a tablet, a powder, a pill, a sachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol, a soft or hard gelatin capsule, a sterilized injectable solution, a sterilized powder, or the like.
  • the composition may be conveniently formulated into a unit dosage form.
  • the composition of the present invention is most preferably an injectable preparation.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount refers to an amount sufficient to treat a disease.
  • the level of the effective dosage can be determined according to the severity of the disease; the age, weight, health, and sex of a patient; the drug sensitivity in a patient; the administration time, route and release rate; the treatment duration; or elements including drugs that are blended or simultaneously used with the composition of the present invention, or other elements well- known in the medical field.
  • the unit dosage of the composition of the present invention for an animal except for a human can be 200 to 10,000 units (IU)/kg of body weight per dose, preferably about 200 to 5,000 units/kg of body weight per dose, more preferably 200 to 2000 units/kg of body weight per dose, and most preferably 500 to 1000 units/kg of body weight per dose.
  • the unit dosage is 20,000 to 45,000 units, preferably 25,000 to 40,000 units, and more preferably 30,000 to 40,000 units, regardless of a body weight.
  • motor neuron diseases refer to diseases which lead to impairment in the motor nerve functions.
  • examples of the motor neuron diseases include amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA).
  • Examples of other neurodegenerative diseases, which are different from the motor neuron diseases include Parkinson's disease, Huntington's disease, multisystem atrophy, Alzheimer's disease, Pick's disease, and olivopontocerebellar atrophy.
  • Examples of the diseases for which the composition of the present invention is effective preferably include amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA), and more preferably amyotrophic lateral sclerosis (ALS).
  • the composition of the present invention is most preferably a composition for treating amyotrophic lateral sclerosis (ALS).
  • the composition of the present invention is highly effective for the treatment of motor neuron diseases. That is, the composition of the present invention shows enhanced motor ability of mice with amyotrophic lateral sclerosis (ALS) which had been administered with the composition of the present invention, as compared with mice which had been not administered with the composition of the present invention, with the enhancement approaching 30%. It also shows enhanced survival ability (survival duration). Further, in the clinical experiment involving the patients with amyotrophic lateral sclerosis (ALS), the patients which had been administered with the composition of the present invention showed clinical changes such as remarkable improvement in the difficulties in deglutition, respiration, and phonation functions, delayed time of maintaining a standing position, and reduced insomnia. Accordingly, the composition of the present invention can be effectively used for treating motor neuron diseases.
  • ALS amyotrophic lateral sclerosis
  • the present invention relates to a method for treating motor neuron diseases, which comprises a step of administering a composition comprising EPO, an EPO fragment, or an analogues thereof to an individual for treating motor neuron diseases.
  • treatment refers to a means for therapeutic treatment, prevention, or amelioration.
  • a person in need of treatment encompasses a person who is suffering from a motor nerve disorder or a motor neuron disease, and a person who tries to prevent a motor nerve disorder or a motor neuron disease.
  • an individual refers to any mammal in need of treatment, including a human and non-human primates, domestic animals and livestock, pet or sports animals, for example, dogs, horses, cats, sheep, pigs, and cows.
  • the present invention relates to a method for treating motor neuron diseases, which comprises a step of parenterally administering the composition comprising EPO to an individual.
  • the present invention relates to a method for treating motor neuron diseases, which comprises a step of simultaneously administering to an individual a composition further comprising of at least one additional factor selected from growth factors such as EPO, FGF, EGF, IGFs, TGFs, and NGF; neurotrophic factors such as BNF and CTF; peptide radiopharmaceuticals; antisense drugs; antibodies to biological activators; immunosuppressants such as cyclosporine; cytokines such as interleukin, interferon, and LIF; and glycogen synthase kinase (GSK) 3-beta inhibitors.
  • the present invention relates to a method for treating motor neuron diseases, which comprises a step of sequentially administering to an individual a composition comprising EPO, and a composition comprising at least
  • EXAMPLE 1 Therapeutic effects of EPO in amyotrophic lateral sclerosis mouse model (SODl mutant transgenic mouse model)
  • mice Five animals from each group were subjected to the experiment, and were observed and compared for the presence of any symptoms of amyotrophic lateral sclerosis such as hands and feet shaking, cramping of muscles, hy- perreflexia, muscle weakness in arms and legs, myoparalysis in arms and legs, and the like.
  • the mice were also subjected to an assessment for motor ability using rotarod (Ugo Basile; Comerio-Varese, Italy) to compare the effects of EPO.
  • a general method was used to measure changes in the motor ability by using a rotarod, and starting from one week before administration, the mice were trained to be adapted to the rotarod machine. As the indices to be measured, the amount of time for the mice to stay on the rotarod, the number of rotations made at the time of falling, and the like were used.
  • the experiment was performed in a way such that 1, 2.5, or 5 IU of EPO per gram of the mouse body weight was intraperitoneally administered at an interval of 2 weeks, and the animals in the control group were intraperitoneally administered with normal saline only in the same manner.
  • the survival time of the amyotrophic lateral sclerosis mouce model was measured in correlation to the amount of EPO administered. Evaluation was based on the survival time which was defined to be limited to the time point when the mouse could not spontaneously stand up within 30 seconds.
  • Nine animals from each group were used in the experiment, and the results are presented in Fig. 2. As a result, it could be confirmed that the survival time increased with the amount of EPO administered in a concentration-dependent manner, and in particular, the longest survival time was recorded when 5,000 IU/kg of EPO was administered.
  • Clinically Definite ALS when all of the upper motor neuron signs and lower motor neuron signs are present in three or more regions.
  • Clinically Probable ALS when all of the upper motor neuron signs and lower motor neuron signs are present in at least two regions, with the former being rostral to the latter
  • Clinically Probable-Laboratory-supported ALS when the upper motor neuron signs and lower motor neuron signs are present in one region, or when the upper motor neuron signs alone are present in one region, with the electromyogramic findings being applicable to the electromyogram criteria in two or more limbs in both cases
  • Clinically possible ALS when the upper motor neuron signs and lower motor neuron signs are present in one region, when the upper motor neuron signs alone are present in two or more regions, or when the lower motor neuron signs are rostral to the upper motor neuron signs
  • Clinically Suspected ALS when definite lower motor neuron signs are present, or when the diagnosis of ALS could not be regarded as sufficiently certain to include the patient in a research study
  • Table 3 the results of therapy are presented in Table 3. As shown in Table 3, the patients administered with rhEPO were not observed to have any abnormal responses in Hb, Hct, PLT count, and blood pressure, as well as in the hepatic and renal functions, and the like.
  • [63] [64] Based on the functional rating scale of the ALS patients selected in Example 2-1 (hereinafter, referred to as 'ALSFRS-r'), those having 20 or more points in the ALSFRS-r score were classified to group A, while those having 20 or less points in the ALSFRS-r score were classified to group B. Group A was classified again into group A-I (rapidly progressing ALS) and group A-II (slowly progressing ALS), depending on the rate of change in the ALSFRS-r score during an observation period of 3 months. The changes in the ALSFRS-r score in group A are presented in Figs. 6 and 7.
  • group A showed definite differences in the amount of change in the ALSFRS-r score for 3 months after EPO administration, as compared with the amount of change in the ALSFRS-r score for 3 months before EPO administration, showing alleviation of the ALS disease.
  • group A-I showed greater changes in the ALSFRS-r score than group A-II, and this implies that the EPO administration according to the present invention can give better effects to patients with rapidly progressing ALS.
  • Fig. 8 the improved symptoms reported by the ALS patients after EPO administration are presented in Fig. 8. Although these symptoms cannot be converted to values to be included in the ALSFRS-r score, the patients reported the improved symptoms after EPO administration. As shown in Fig. 8, many patients reported feelings of improvement in muscle power of the limbs and feelings of improvement in respiration, oral function, sialorrhea and the like.
  • FIG. 9 shows the results of neurophysiological assessment using a neurophys- iological index (ulnar nerve,both). As shown in Fig. 9, there were no statistically meaningful changes for 2 months after EPO administration, but there were differences in the amount of change from the time point of after 3 months. This implies that the effect of EPO administration of two times could be maintained for about 1 month. [68]
  • composition for treating motor neuron diseases comprising EPO or an analogue thereof according to the present invention is effective in the treatment of motor neuron diseases, particularly amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Neurology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition destinée au traitement des maladies des motoneurones, et plus particulièrement, la sclérose latérale amyotrophique (SLA). Cette composition est à base d'érythropoïétine (EPO), d'un fragment d'érythropoïétine, ou d'un de ses analogues. L'invention concerne un procédé destiné au traitement des maladies des motoneurones au moyen de cette composition. La composition et le traitement de l'invention peuvent constituer une thérapie efficace contre les maladies des motoneurones, en particulier contre la sclérose latérale amyotrophique (SLA).
PCT/KR2006/005065 2006-05-24 2006-11-28 Procédé et compositions à base d'érythropoïétine pour traiter les maladies des motoneurones WO2007136155A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2006-0046687 2006-05-24
KR20060046687 2006-05-24

Publications (1)

Publication Number Publication Date
WO2007136155A1 true WO2007136155A1 (fr) 2007-11-29

Family

ID=38723456

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/005065 WO2007136155A1 (fr) 2006-05-24 2006-11-28 Procédé et compositions à base d'érythropoïétine pour traiter les maladies des motoneurones

Country Status (2)

Country Link
KR (1) KR20070113086A (fr)
WO (1) WO2007136155A1 (fr)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JUNK A.K. ET AL.: "Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury", PROC. NATL. ACAD. SCI. U.S.A., vol. 99, no. 16, 2002, pages 10659 - 10664, XP008090830 *
LIU R. ET AL.: "Intrinsic and extrinsic erythropoietin enhances neuroprotection against ischemia and reperfusion injury in vitro", J. NEUROCHEM., vol. 96, no. 4, February 2006 (2006-02-01), pages 1101 - 1110, XP008092216 *

Also Published As

Publication number Publication date
KR20070113086A (ko) 2007-11-28

Similar Documents

Publication Publication Date Title
Svensson et al. Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia
US10966962B2 (en) Method for treating neurodegenerative diseases
US7723302B2 (en) Method of treating Parkinson's disease
CN107660147A (zh) 用于治疗帕金森病和相关障碍的组合物
KR20190132585A (ko) 근위축성 측색경화증의 치료 또는 병세 진전 억제를 위한 약제
CN111032027B (zh) 使用烟酰胺核糖核苷治疗和预防运动神经元疾病
KR101903713B1 (ko) 만성 외상성 뇌병증-ii를 예방 및/또는 치료하는 방법
US20240173341A1 (en) Composition for ameliorating or treating dementia containing 2'-fucosyllactose
JP6262661B2 (ja) 筋萎縮性側索硬化症治療剤
WO2007136155A1 (fr) Procédé et compositions à base d'érythropoïétine pour traiter les maladies des motoneurones
CN113166721A (zh) 抑郁症治疗方法和药物
Hinsie The treatment of schizophrenia: A survey of the literature
US20190247405A1 (en) Treatment of sma
WO2008093942A1 (fr) Méthodes et compositions contenant l'érythropoïétine pour le de traitement des maladies du motoneurone
Jin et al. Effect of recombinant human growth hormone add on therapy on acute stroke outcome
KR20240006282A (ko) 모과 추출물을 유효성분으로 함유하는 우울증의 개선, 예방 또는 치료용 조성물
Hohorst et al. Estrous phase during fear extinction modulates fear relapse through a nigrostriatal dopamine pathway
US20180263993A1 (en) Method for preventing and/or treating chronic traumatic encephalopathy-iv
CN114502157A (zh) 抑制肌肉量的降低、预防其降低、维持、恢复或增加肌肉量用组合物
Argyriou et al. Cocaine use and abuse triggering sporadic young-onset amyotrophic lateral sclerosis
WO2012137645A1 (fr) Agent préventif et/ou thérapeutique pour l'allodynie provoquée par un agent anti-cancer
WO1998026778A1 (fr) Medicaments pour traiter/prevenir les mouvements anormaux qui accompagnent les troubles du systeme nerveux extrapyramidal
KR20070032071A (ko) 중추 신경 질환 발증 후의 기능 장해의 회복 촉진제

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06823773

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06823773

Country of ref document: EP

Kind code of ref document: A1