WO2010018856A1 - Agent prophylactique/d’amélioration ou thérapeutique destiné aux maladies associées au récepteur des cannabinoïdes - Google Patents

Agent prophylactique/d’amélioration ou thérapeutique destiné aux maladies associées au récepteur des cannabinoïdes Download PDF

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WO2010018856A1
WO2010018856A1 PCT/JP2009/064292 JP2009064292W WO2010018856A1 WO 2010018856 A1 WO2010018856 A1 WO 2010018856A1 JP 2009064292 W JP2009064292 W JP 2009064292W WO 2010018856 A1 WO2010018856 A1 WO 2010018856A1
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receptor
group
epa
ameliorating
cannabinoid
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PCT/JP2009/064292
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Japanese (ja)
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秀生 兼廣
浩之 河野
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持田製薬株式会社
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    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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Definitions

  • the present invention relates to an agent for preventing / ameliorating or treating a disease involving cannabinoid receptors, and a method for using the same. More particularly, the present invention relates to an agent for preventing / ameliorating or treating a disease particularly involving cannabinoid 1 receptor, and a method for using the same.
  • the present invention relates to a preventive or alleviating agent for side effects caused by a cannabinoid receptor ligand, and a method for using the same. More specifically, the present invention relates to a preventive or alleviating agent for side effects caused by a cannabinoid 1 receptor ligand, and a method for using the same.
  • Cannabinoid (hereinafter referred to as “CB”) is a general term for ⁇ 9 -tetrahydrocannabinol (hereinafter referred to as “ ⁇ 9 -THC”), which is the main active ingredient of cannabis, and its similar compounds (Non-patent Document 1). ).
  • CB is known to cause various effects on mammals such as confusion of time sensation and spatial sensation, euphoria, hallucination, somnolence, increased appetite, decreased pain sensation, immunosuppression, and anti-inflammation (non-) Patent Document 2).
  • Non-patent Document 3 discloses that a receptor for CB exists in 1988, and many of these actions are receptors. It came to be thought that through.
  • CB receptor As a cannabinoid receptor (hereinafter referred to as “CB receptor”), in 1990, Matsuda et al. (Non-patent Document 4) disclosed a cannabinoid 1 receptor (hereinafter referred to as “CB1 receptor”) in 1993. Munro et al. (Non-patent Document 5) have cloned cannabinoid 2 receptors (hereinafter referred to as “CB2 receptors”), respectively, and two subtypes have been identified to date.
  • CB2 receptors cannabinoid 1 receptor
  • CB1 receptor is expressed in most nervous system tissues and is involved in inhibitory control of neurotransmission.
  • the CB2 receptor is hardly expressed in the central nervous system such as the brain, and is expressed in a large amount in tissues and cells mainly involved in inflammatory reaction or immune response such as spleen and tonsils.
  • actions such as confusion of time and space sensation, euphoria, hallucinations, somnolence, and appetite increase are mediated through CB1 receptors in the central nervous system Has been revealed.
  • the actions such as a decrease in pain sensation, immunosuppression, and anti-inflammation are considered to be actions mediated by cells that participate in immune responses or inflammatory reactions expressing CB2 receptors. It has been.
  • dronabinol (trade name: MARINOL (registered trademark), Unimed Pharmaceuticals, Inc., Marietta, GA, USA) which is ⁇ 9 -THC and CB1 receptor Rimonabant (trade name in the European Union (EU) region: ACOMPLIA (registered trademark), Sanofi-Aventis, Paris, France), etc.
  • CB receptor ligands (such as agonists, antagonists or inverse agonists) are being applied as pharmaceuticals.
  • rimonabant (Acompria (registered trademark)
  • Non-patent Document 7 Non-patent Document 7
  • rimonabant side effects of rimonabant include upper respiratory tract infection, sinusitis, gastroenteritis, depressive disorders (such as depression, manic depression, depression), mood swings with depressive symptoms, anxiety, irritation, hypersensitivity, sleep disorders, Insomnia, abnormal insomnia, panic symptoms, anger, dissatisfaction, emotional disorder, suicide attempt, aggression, aggressive behavior, hallucinations, memory loss (amnesia), attention deficit, dizziness, immobility dizziness, hyposensory, sciatica, Dyssensory, lethargy, flushing, hiccups, nausea, diarrhea, vomiting, loss of appetite, loss of appetite, stomach discomfort, thirst, pruritus, excessive sweating, night sweats, tendonitis, muscle spasm, muscle spasm, asthenia /
  • headache, euphoria, fatigue, insomnia and the like as symptoms of fatigue, influenza, falls, bruises, sprains, and overdose Non-patent Document 7).
  • ⁇ 9 -THC is not present in the animal body. Nevertheless, the presence of the CB receptor suggested the presence of an endogenous CB receptor ligand.
  • Non-Patent Document 9 As a result of searching for an endogenous CB receptor ligand, Devane et al. (Non-Patent Document 9) in 1992 introduced arachidonic acid, which is a polyunsaturated fatty acid (hereinafter referred to as “PUFAs”), from porcine brain.
  • Anandamide also known as N-arachidonoylethanolamine
  • Sugiura et al. (Non-Patent Document 10) in 1995 from rat brain and Mechoulam et al.
  • 2-arachidonoylglycerol (hereinafter referred to as “2-AG”) in which arachidonic acid was ester-bonded to position 2 of glycerol from the small intestine of dogs, respectively, and endogenous CB reception. Reported as a body ligand.
  • Non-Patent Documents 12 and 13 show that glycerol in which arachidonic acid of 2-AG is substituted with PUFAs having 20 or more carbon atoms and 3 or more unsaturated bonds also has an agonistic action on CB1 and 2 receptors.
  • In-vitro studies report that icosatrienoic acid, icosapentoic acid (hereinafter referred to as “EPA”) or docosahexaenoic acid (hereinafter referred to as “DHA”) are in the second position of glycerol.
  • EPA icosatrienoic acid
  • DHA docosahexaenoic acid
  • Examples include 2-eicosatrienoylglycerol, 2-eicosapentaenoylglycerol (hereinafter referred to as “2-EG”), 2-docosahexaenoylglycerol (hereinafter referred to as “2-DG”), and the like. ing.
  • PUFA having the first double bond at the third position from the methyl group side is called ⁇ 3 PUFAs, and examples thereof include ⁇ -linolenic acid, EPA and DHA.
  • EPA-E EPA ethyl ester
  • EPADEL EPA ethyl ester
  • DHA-E DHA ethyl ester
  • Soft capsules (trade name: Lovaza (registered trademark), GlaxoSmithKline (London, UK)) containing about 37.5% by mass of active ingredient for treatment of hypertriglyceridemia It is commercially available as an agent in the United States.
  • the present invention relates to prevention / amelioration of CB receptor-related diseases that are highly safe, effective, and easy to use for the prevention / amelioration or treatment of diseases involving CB receptors, particularly CB1 receptors. It is an object to provide a therapeutic agent and a method of using the same.
  • the present invention also relates to a CB receptor ligand, particularly a CB1 receptor ligand, which is highly safe, effective and easy to use for use in the prevention or reduction of side effects caused by a CB receptor ligand, particularly a CB1 receptor ligand. It is an object of the present invention to provide a preventive or alleviating agent for side effects caused by the above and a method for using the same.
  • At least one compound selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof exhibits a neutral antagonist-like action on the CB receptor, particularly the CB1 receptor, and the CB receptor. It has been found that it has a preventive / ameliorating or therapeutic effect on a related disease, and has a preventive or alleviating effect on side effects of CB receptor ligands, particularly CB1 receptor ligands, and has completed the present invention.
  • the agent for preventing / ameliorating or treating CB receptor-related diseases and the agent for preventing or reducing side effects caused by CB receptor ligands provided by the present invention are from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof. It contains at least one selected compound as an active ingredient. Examples of embodiments of the present invention are shown below.
  • a preventive / ameliorating or treating agent for CB receptor-related diseases comprising as an active ingredient at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof.
  • ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof are at least one compound selected from the group consisting of EPA, DHA and ⁇ -linolenic acid and pharmaceutically acceptable salts and esters thereof ( The preventive / ameliorating or therapeutic agent according to any one of 1) to (4). (6) The preventive / ameliorating or treating agent according to any one of (1) to (4) above, which contains EPA-E and / or DHA-E as the ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof . (7) The preventive / ameliorating or therapeutic agent according to any one of (1) to (4) above, which contains EPA-E as the ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof.
  • An agent for preventing or alleviating side effects caused by a CB receptor ligand comprising as an active ingredient at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof.
  • the CB1 receptor agonist is anandamide, 2-AG, dronabinol, nabinoximol, AZ-599, AZD-1940, GW-1000, KN-38-7271, O-1057, Org-28611, Org-26828, SCH-
  • the prophylactic or alleviating agent according to (9) above which is at least one compound selected from the group consisting of 900111 and SAB-378.
  • the CB1 receptor antagonist or inverse agonist is ⁇ 9 -tetrahydrocannabivaline, drinaban, rimonabant, sulinaban, otenaban, ibipinavan, taranaban, AZD-2207, AZD-1175, CIS-565C, Org-50189, TM-38837,
  • the prophylactic or alleviating agent according to (11) above which is at least one compound selected from the group consisting of V-25343 and ZYO-1.
  • the side effect of the CB1 receptor ligand is at least one selected from the group consisting of nausea, mood swings associated with depressive symptoms, anxiety, immobility, suicide attempts, eating disorders, and drug dependence. Or the preventive or alleviating agent according to any one of (13).
  • the CB receptor ligand is a CB2 receptor ligand.
  • a method for preventing / ameliorating or treating a CB receptor-related disease comprising a step of administering at least one compound selected from the group consisting of ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof.
  • the CB receptor-related disease is a CB1 receptor-related disease.
  • the CB receptor-related disease is a CB2 receptor-related disease.
  • (22) A method for preventing or alleviating a side effect caused by a CB receptor ligand, comprising a step of administering at least one compound selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof. (23) The method according to (22) above, further comprising administering a CB receptor ligand. (24) The method according to (23) above, wherein the two administration steps are performed simultaneously. (25) The method according to (23) above, wherein the two administration steps are performed at different times. (26) The method according to any one of (22) to (25) above, wherein the CB receptor ligand is a CB1 receptor antagonist or inverse agonist.
  • the CB1 receptor-related disease is at least one selected from the group consisting of postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders, and abnormal taste (taste) 30) Use.
  • the CB receptor-related disease is a CB2 receptor-related disease.
  • the use according to (33) above, wherein the CB receptor-related disease is a CB1 receptor agonist.
  • a CB receptor ligand By using at least one compound selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof, a CB receptor ligand, particularly a CB1 receptor, which is highly safe, effective and easy to use.
  • An agent for preventing or alleviating a side effect caused by a ligand, and a method of using the same can be provided.
  • CB receptor ligands can be reduced by the present invention, and treatment can be continued in patients who have failed to administer CB receptor ligands due to these side effects or who have had to be interrupted. it can.
  • CB1 receptor neutral antagonist-like action resulting in excessive CB1 receptor such as postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorder or abnormal taste (taste) It is useful for preventing / ameliorating or treating a syndrome, disorder or disease caused by enhancement or excessive suppression. It is also useful for preventing or reducing side effects caused by CB1 receptor ligand (agonist, antagonist or inverse agonist).
  • EPA-E is expected to prevent / ameliorate or treat nicotine dependence or postoperative cognitive impairment by inhibiting CB1 receptor hyper-enhancement through CB1 receptor neutral antagonist-like action (Animal model test 1 and clinical model test 1).
  • Tic disorders, Tourette's syndrome, refractory hiccups or abnormal taste (taste) are thought to be associated with CB1 receptor suppression (Non-Patent Documents 6 and 7 and Physiology and Behavior, 2007) , 90, p.425-430), EPA-E inhibits CB1 receptor over-suppression through CB1 receptor neutral antagonist-like action, thereby inhibiting tic disorder, Tourette syndrome, refractory hiccups or taste (taste) ) Is expected to be prevented / ameliorated or treated (clinical model test 2 and animal model test 2).
  • the present invention is a preventive / ameliorating or treating agent for CB receptor-related diseases comprising at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof, and a method of using the same.
  • the present invention also relates to a preventive or alleviating agent for side effects caused by a CB receptor ligand comprising at least one selected from the group consisting of ⁇ 3 PUFAs and pharmaceutically acceptable salts and esters thereof, and a method of using the same. .
  • ⁇ 3 PUFAs is used to mean not only ⁇ 3 PUFAs but also ⁇ 3 PUFAs derivatives such as pharmaceutically acceptable salts or esters thereof.
  • ⁇ 3PUFAs is used in the ordinary sense known to those skilled in the art, and among the fatty acids having a plurality of carbon-carbon double bonds in the molecule, the first double is in the third position counted from the methyl group side. It refers to PUFAs that have bonds.
  • Preferred ⁇ 3 PUFAs are exemplified by EPA, DHA and ⁇ -linolenic acid, more preferably EPA and / or DHA.
  • Examples of the pharmaceutically acceptable salt include salts with an inorganic base such as sodium salt or potassium salt, an organic base such as benzylamine salt or diethylamine salt, or a basic amino acid such as arginine salt or lysine salt.
  • an inorganic base such as sodium salt or potassium salt
  • an organic base such as benzylamine salt or diethylamine salt
  • a basic amino acid such as arginine salt or lysine salt.
  • esters examples include alkyl esters with ethyl or ethanolamine, mono-, di- or tri-glycerol esters, or phospholipid esters such as phosphatidylcholine or phosphatidylethanolamine.
  • Preferred ⁇ 3 PUFAs derivatives include EPA-E, DHA-E, 2-EG, 2-DG, N-icosapentaenoylethanolamine, and N-docosahexaenoylethanolamine, more preferably EPA-E. And / or DHA-E is presented.
  • ⁇ 3 PUFAs used in the present invention may be a synthetic product, a semi-synthetic product or a natural product, or may be in the form of a natural oil containing them.
  • the natural product means a product extracted from a natural oil containing ⁇ 3 PUFAs by a known method, a product that has been refined, or a product that has been further refined.
  • Semi-synthetic products include PUFAs produced by microorganisms and the like, and those obtained by subjecting the PUFAs or natural PUFAs to chemical treatment such as esterification or transesterification.
  • ⁇ 3PUFAs one of these can be used alone, or two or more can be used in combination.
  • the purity of ⁇ 3 PUFAs is not particularly limited, but usually, the content of ⁇ 3 PUFAs in the total fatty acids of the composition of the present agent is preferably 25% by mass or more, more preferably 50% by mass or more, still more preferably 70% by mass or more, even more preferably. Is 85% by mass or more, and it is particularly preferable that the present composition is substantially free of other fatty acid components other than ⁇ 3 PUFAs.
  • the composition ratio of EPA-E / DHA-E and the content ratio of EPA-E + DHA-E in all fatty acids are not particularly limited, but a preferred composition ratio is EPA-E.
  • / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and further preferably 1.2 or more.
  • EPA-E and / or DHA-E are preferably of high purity.
  • the EPA-E and / or DHA-E content ratio in the total fatty acids and derivatives thereof is preferably 40% by mass or more, more preferably 55% by mass or more, further preferably 84% by mass or more, The thing of 96.5 mass% or more is still more preferable.
  • the purity of ⁇ 3 PUFAs in all fatty acids is preferably high, the EPA + DHA purity which is ⁇ 3 PUFAs is more preferable, and the purity of EPA is more preferable.
  • the content of other long chain saturated fatty acids is preferably low.
  • the content of ⁇ 6 long chain unsaturated fatty acids, particularly arachidonic acid is preferably small, more preferably less than 2% by mass, and even more preferably less than 1% by mass.
  • EPA-E and / or DHA-E used in the preventive / ameliorating or therapeutic agent or preventive or alleviating agent of the present invention is more effective against cardiovascular events such as saturated fatty acids and arachidonic acid than fish oil or fish oil concentrate.
  • cardiovascular events such as saturated fatty acids and arachidonic acid than fish oil or fish oil concentrate.
  • vitamin A since it is an ester, it has a higher oxidation stability than fish oil or the like, which is mainly a triglyceride, and a sufficiently stable composition can be obtained by adding a normal antioxidant.
  • the cardiovascular event is used in the ordinary sense known to those skilled in the art and includes cardiovascular death (such as fatal myocardial infarction or sudden cardiac death), non-fatal myocardial infarction, reinfarction, unstable angina.
  • cardiovascular death such as fatal myocardial infarction or sudden cardiac death
  • non-fatal myocardial infarction such as myocardial infarction or sudden cardiac death
  • non-fatal myocardial infarction such as fatal myocardial infarction or sudden cardiac death
  • non-fatal myocardial infarction such as congestive heart failure, stroke, cerebral infarction, or fainting, or treatment such as coronary artery bypass grafting (CABG), percutaneous coronary angioplasty (PTCA), or stent
  • CABG coronary artery bypass grafting
  • PTCA percutaneous coronary angioplasty
  • stent includes illustratively.
  • Epadale for example, Epadale (Mochida Pharmaceutical) available in Japan can be used.
  • the mixture of EPA-E and DHA-E can be obtained by using, for example, Lovaza (registered trademark) (Glaxo SmithKline) commercially available in the United States.
  • Lovaza registered trademark
  • Gaxo SmithKline commercially available in the United States.
  • Refined fish oil can also be used as ⁇ 3 PUFAs.
  • ⁇ 3PUFAs monoglyceride, diglyceride, triglyceride, or a combination thereof is one of the preferred embodiments.
  • Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International plc, England), as well as EPAX6000FA, EPAX5000TG, EPAX4520TG50, EPAX4510T50, EPAX4510T , K85EE and K80EE (Pronova BioPharma ASA, Lysaker, Norway) containing various ⁇ 3 PUFAs or salts or esters thereof are commercially available and can be obtained and used.
  • CB receptor means known CB receptors, CB1 receptor and CB2 receptor, as well as amino acid sequence and structural / functional similarity between those skilled in the art and CB1 receptor or CB2 receptor (7th membrane A receptor capable of recognizing a penetrating type, a G protein-coupled type, and the like, and is used to mean a receptor to which ⁇ 9 -THC or an analog thereof binds.
  • the CB receptor referred to in the present invention is similar to the CB1 receptor or the CB2 receptor, includes a receptor to which ⁇ 9 -THC or a similar compound binds, and is a known CB receptor, the CB1 receptor or the CB2 It is not limited to receptors only. For example, since a CB1 receptor agonistic action is observed in a CB1 receptor knockout mouse, the existence of a new CB receptor is presumed, and such an unidentified CB receptor is also included.
  • analogous compounds of delta 9 -THC compounds having agonist activity to those skilled in the art can recognize structural similarity to delta 9 -THC compounds or CB1 receptor and / or CB2 receptors Any other compound may be used as long as the compound is known to date.
  • the analog of ⁇ 9 -THC referred to in the present invention includes cannabinol, cannabidiol, cannabigerol, cannabicycrol, and other natural cannabinoids and anandamide , 2-AG, 2-arachidonyl glyceryl ether, virodhamine, palmitoic ethanolamide and N-archydonyl-dopamin Cannabinoids (also referred to as “endogenous cannabinoids”), and A-41988 (also known as BW29Y), ajulemic acid (also known as CT-3, HU-239), AM-087, AM-411, AM- 855, AM-905, AM-906, M-919, AM-938, AM-4030, AMG-1, AMG-3, AMG-36, AMG-41, dexanabinol (HU-211), dimethylheptylpyran, HU-210, JWH- 051, JWH-133, JWH-139, L
  • CB receptor-related disease is used to include biological reactions mediated by CB receptors and related syndromes, disorders and diseases.
  • CB receptor-related diseases include eating, obesity, metabolism, diabetes, glaucoma, social or mood, seizures, drug abuse, caused by excessive or excessive suppression of CB1 receptor and / or CB2 receptor, Includes syndromes, disorders and diseases related to learning / cognition or memory, organ contraction, muscle spasm, gastrointestinal tract and viscera, respiratory organs, locomotor activity or exercise, immunity and inflammation, cell proliferation, pain, and neurodegeneration .
  • Syndromes, disorders and diseases related to eating include bulimia, anorexia, obesity, weight loss, weight gain, unregulated appetite, poor appetite in cancer, AIDS, cachexia, and taste (taste). Abnormalities are included.
  • Syndrome, disorders and diseases associated with obesity include heredity, diet, excess food intake, metabolic syndrome, and hypothalamic disorder or disease, and aging, reduced motor activity, abnormal fat mass distribution, and / or Obesity as a result of abnormal fat compartment distribution and the like is included.
  • Metabolic syndromes, disorders and diseases include metabolic syndrome, dyslipidemia (hypercholesterolemia, hypertriglyceridemia, high LDL cholesterolemia, low HDL cholesterolemia), atherosclerosis, fatty liver , Hepatitis (viral, alcoholic, non-alcoholic, drug), hypertension, diabetes, insulin sensitivity or resistance, and hyperinsulinemia.
  • dyslipidemia hypercholesterolemia, hypertriglyceridemia, high LDL cholesterolemia, low HDL cholesterolemia
  • atherosclerosis fatty liver
  • Hepatitis viral, alcoholic, non-alcoholic, drug
  • hypertension diabetes
  • insulin sensitivity or resistance and hyperinsulinemia.
  • Syndrome, disorder and disease related to diabetes include glucose regulation abnormality, insulin resistance, glucose tolerance abnormality, hyperinsulinemia, dyslipidemia, hypertension, obesity and the like.
  • Type II diabetes is associated with persistent plasma hyperglycemia, polyuria, polyposis, bulimia and chronic microvascular complications such as retinopathy, nephropathy and neuropathy, and dyslipidemia and hypertension. Characterized by clinical signs or symptoms such as macrovascular complications. These micro and macrovascular complications can result in blindness, end-stage renal disease, limb amputation and / or myocardial infarction.
  • Metabolic syndrome is the development of type II diabetes including impaired glucose tolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypertension and obesity, and cerebrovascular disorders such as cardiovascular disease, cerebral infarction and cerebral hemorrhage It is an obstacle that presents risk factors.
  • Syndrome, disorder and disease related to glaucoma include increased intraocular pressure, ocular circulation disorder, optic nerve disorder, rainbow vision, decreased visual acuity, eye pain, visual impairment such as visual field, and blindness.
  • Syndrome, disorder and disease related to society or mood include psychosis in general, depression, manic depression, bipolar disorder, anxiety, schizophrenia, mood disorder, delirium, social affective or cognitive impairment, obsession or urgency Neurosis, adult personality disorder, shock behavior disorder, panic disorder, phobia, confusion, neurological stress disorder, post-traumatic stress disorder (PTSD), attention deficit disorder (ADD / ADHD), hyperactivity, autism, speechlessness, Behavioral addiction, arousal disorder, insomnia, intuition, illusion disorder, and reduced motivation are included.
  • Syndrome, disorder and disease related to drug abuse include alcohol, amphetamines (amphetamine, methamphetamine, etc.), barbiturates (barbitur derivatives, benzodiazepine derivatives, etc.), cannabis (marijuana, hashish, etc.), ***e, hallucinogen (LSD , Mescarin, sirocibin, phencyclidine, etc.), carts, opiates (morphine, heroin, codeine, pethidine, fentanyl, etc.) or organic solvents (toluene, thinner, acetone, ether, chloroform, benzene, etc.) ⁇ Withdrawal symptoms and nicotine or tobacco abuse / dependence / withdrawal symptoms are included.
  • Syndrome, disorder and disease related to learning, cognition or memory include memory loss or impairment as a result of aging, disease and / or drug side effects (adverse events), and cognitive impairment, postoperative cognitive decline ( Confusion, delirium, phantom limb, phantom limb pain, etc.), senile / vascular / alzheimer-type dementia symptoms, amnesia, and forgetting.
  • Syndrome, disorder and disease related to muscle spasms include multiple sclerosis, cerebral palsy, tremor, and infantile febrile convulsions.
  • Spontaneous movements or movement-related syndromes, disorders and diseases include seizures, Parkinson's disease, Parkinson's dyskinesia, multiple sclerosis, epilepsy, motor dysfunction such as levodopa-induced movement disorders, catalepsy, Tourette's syndrome, and tic disorders Etc. are included.
  • Gastrointestinal and visceral-related syndromes, disorders and diseases include gastrointestinal ulcers, gastrointestinal inflammation, gastrointestinal dysmotility-related disorders (with or without pain, diarrhea or constipation), hypersensitivity Bowel syndrome (and other forms of intestinal dysfunction), inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), celiac disease, kidney disease such as renal failure, liver fibrosis, cirrhosis, and urinary tract / bladder Functional impairments are included.
  • Respiratory syndromes, disorders and diseases include chronic pulmonary obstructive disease, emphysema, inflammatory pneumonia, pulmonary fibrosis, asthma, bronchitis, airway obstruction, sleep apnea, and refractory hiccups Is included.
  • Syndrome, disorder and disease related to immunity and inflammation include allergy, arthritis, rheumatoid arthritis, dermatitis, autoimmune disease, immunodeficiency and chronic neuropathic pain.
  • Syndromes, disorders and diseases related to cell proliferation include benign or malignant unregulated cell growth (invasive growth), such as pharyngeal cancer, tongue cancer, esophageal cancer, gastric cancer, duodenal cancer, colon cancer, rectal cancer, Lung cancer, liver cancer, pancreatic cancer, kidney cancer, spleen cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, skin cancer, brain tumor, osteosarcoma, leukemia, or lymphoma, and pain caused by cancer or cachexia • Anorexia, weakness, hypercalcemia, and nausea, nausea, and vomiting caused by anticancer drugs are included.
  • invasive growth such as pharyngeal cancer, tongue cancer, esophageal cancer, gastric cancer, duodenal cancer, colon cancer, rectal cancer, Lung cancer, liver cancer, pancreatic cancer, kidney cancer, spleen cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, skin cancer, brain tumor, osteosarcoma,
  • Pain-related syndromes, disorders and diseases include neuropathic pain mediated by central and peripheral pathways, chronic pain, bone and joint pain, migraine-related pain, cancer pain, menstrual pain, labor pain, phantom limb pain , Pruritus, and enhancement of narcotic and non-narcotic analgesics.
  • Syndromes, disorders and diseases associated with neurodegeneration include Parkinson's disease, Huntington's chorea, multiple sclerosis, hemorrhoids, traumatic head or brain ischemia or secondary biochemical damage associated with neuropathy, Includes Guillain-Barre syndrome, head trauma, spinal cord injury, neuroprotection in neurodegenerative diseases, infant brain developmental disorders / excitement, oxygen deprivation and ischemic brain inflammation due to nerve gas damage, eye damage and seizures, etc. .
  • endotoxin shock hemorrhagic shock
  • hypotension hypothermia
  • nausea due to emetics migraine, Raynaud's disease, premenstrual syndrome or late corpus luteum syndrome, infertility, premature birth, miscarriage, male and female sexual dysfunction, infection , Chronic fatigue syndrome, and osteoporosis.
  • the preventive / ameliorating or therapeutic agent of the present invention preferably prevents / improves CB1 receptor-related diseases, more preferably postoperative cognitive decline, nicotine dependence, refractory hiccups, tic disorders or abnormal taste (taste) or Used for treatment.
  • CB receptor ligand is used to mean a compound that binds to a CB receptor and causes a biological reaction.
  • the ligands are classified into agonists and antagonists or inverse agonists depending on the reaction expression pattern, and these are included.
  • Both CB1 and CB2 receptor agonists include endocannabinoids such as anandamide and 2-AG, and dronabinol, GW-1000 (trade name: Satibex (registered trademark), GW Pharmaceuticals (GW) Pharmaceuticals plc, Wiltshire, UK)), and O-1057 (Organix Inc., Woburn, MA, USA)).
  • Agonists specific for the CB1 receptor include AZ-599, AZD-1940 (AstraZeneca), KN-38-7271 (Bayer AG), Org-28611, Org-26828, and SCH-900111. (Organon Biosciences Organon BioScience NV, Oss, The Netherlands) and SAB-378 (Novartis Pharma Novartis Pharma AG, Basel, Switzerland).
  • Examples of agonists specific for the CB2 receptor include GW-842166X (GlaxoSmithKline) and S-777469 (Yoshio Shionogi).
  • CB1 and CB2 receptor antagonists or inverse agonists examples include ⁇ 9 -tetrahydrocannabinalin (GW Pharmaceuticals).
  • CB1 receptor specific antagonists or inverse agonists include drinabant, rimonabant and surinabant (Sanofi-aventis), otenabant (Pfizer Pfizer Inc., New York, NY, USA), AZD-2207.
  • CB2 receptor-specific antagonists include AM-630 (University of Connecticut, Storm, CT).
  • the CB receptor ligand referred to in the present invention is not limited to these.
  • a “CB receptor neutral antagonist” does not affect the equilibrium state of the inactive and active forms of the CB receptor, ie it does not affect the CB receptor in any way, but to either a CB receptor agonist or an inverse agonist. However, it is also used to mean an antagonist that competitively antagonizes. Many of the conventional antagonists are inverse agonists that move the equilibrium between the inactive and active forms of the receptor to the inactive side. Symptoms worsen further when antagonists with strong inverse agonist activity are used due to continuous use or drug withdrawal. Rebound phenomenon is likely to occur. On the other hand, a neutral antagonist is considered not to cause inconvenience associated with continuous use in such an inverse agonist.
  • side effect due to CB receptor ligand is used to mean a reaction unfavorable for a living body among biological reactions caused by administration of a CB receptor ligand. Examples include excessive enhancement by CB receptor agonists, excessive suppression by CB receptor antagonists or inverse agonists, and development of tolerance due to long-term use of CB receptor ligands and rebound phenomenon due to discontinuation of use.
  • CB1 receptor ligand examples include upper respiratory tract infection, sinusitis, gastroenteritis, and depressive disorders (depression, manic depression, depression, etc.) reported as side effects of rimonabant, which is an inverse agonist of CB1 receptor.
  • Mood swings with depressive symptoms anxiety, irritation, irritability, sleep disorder, insomnia, abnormal insomnia, panic symptoms, anger, dissatisfaction, euphoria, emotional disorder, suicide attempt, aggressiveness, aggressive behavior, hallucinations, Headache, memory loss (amnesia), attention deficit, dizziness, immobility, hyposensory, sciatica, sensory dysfunction, lethargy, flushing, hiccup, nausea, diarrhea, vomiting, loss of appetite, loss of appetite, stomach discomfort , Dry mouth, pruritus, hyperhidrosis, night sweats, tendonitis, muscle spasms, muscle spasms, asthenia / fatigue, influenza, falls, bruises and sprains.
  • the most frequently reported adverse reactions include upper respiratory tract infection, gastroenteritis, depressive disorder, mood swings with depressive symptoms, anxiety, irritation, irritability, sleep disorder, insomnia, abnormal insomnia, suicide attempt , Memory loss (amnesia), dizziness, hypoxia, sciatica, sensory abnormalities, flushing, nausea, diarrhea, vomiting, itching, hyperhidrosis, tendonitis, muscle spasm, muscle spasm, asthenia / fatigue, falls, Examples include bruises and sprains, and examples of serious side effects include depressive disorder and suicide attempts.
  • dronabinol a CB1 and CB2 receptor agonist
  • lethargy palpitation
  • tachycardia vasodilation / facial flushing
  • conjunctivitis hypotension
  • abdominal pain nausea, vomiting, diarrhea, incontinence
  • amnesia anxiety, nerve
  • nerve Examples include hypersensitivity, ataxia, confusion, depression, dizziness, uplifting, euphoria, hallucinations, paranoia, drowsiness, abnormal thinking, nightmares, language disturbances, tinnitus, drug dependence, flushing, and visual abnormalities.
  • side effects with high incidence include lethargy, palpitation, tachycardia, vasodilation / facial flushing, abdominal pain, nausea, vomiting, amnesia, anxiety, hypersensitivity, ataxia, confusion, depression, dizziness, uplifting feeling Euphoria, hallucinations, paranoia, sleepiness, abnormal thinking, etc.
  • severe side effects include hypotension, confusion, depression, hallucinations, and drug dependence.
  • the preventive or alleviating agent of the present invention is preferably a side effect of CB1 receptor agonist or inverse agonist, more preferably nausea, mood swings associated with depressive symptoms, anxiety, immobility, suicide attempt, eating disorder, memory disorder or drug Used to prevent or reduce side effects such as addiction.
  • the form of the preventive or alleviating agent of the present invention is not particularly limited.
  • a preparation containing ⁇ 3 PUFAs as a single active ingredient (2) a single preparation obtained by co-formulation of ⁇ 3 PUFAs and a CB receptor ligand, (3)
  • the method for preventing or reducing the side effects caused by the CB receptor ligand is not particularly limited, and may include a step of administering ⁇ 3 PUFAs.
  • a method of using a combination of ⁇ 3PUFAs and a CB receptor ligand including a step of administering ⁇ 3PUFAs and a step of administering a CB receptor ligand is also included.
  • ⁇ 3 PUFAs and CB receptor ligands When used in combination, it should be administered as a combination containing both ⁇ 3 PUFAs and CB receptor ligands, and ⁇ 3 PUFAs and CB receptor ligands should be administered separately as separate preparations at the same time or separately at different times. Including.
  • the term “combination” is not necessarily limited to the case where it is simultaneously present in the patient's body, for example, blood, but in the present invention, “combination” means that the action / effect of either one of the drugs is expressed in the patient's body. In this state, the other drug is administered. It is a usage mode in which the prevention or alleviation effect of the CB receptor is obtained using the preventive or alleviating agent of the present invention. Preferably, a usage mode that coexists in the patient's body, for example, in the blood, is desirable, and a usage mode in which the other drug is administered to the patient within 24 hours after the administration of one drug is preferable. .
  • both drugs may be mixed immediately before the administration, may be administered separately, or can be used by shifting the administration time systematically for various purposes.
  • one drug is administered and the other drug is administered and acted at the time when the effect starts to appear or when the effect is fully manifested.
  • one drug particularly CB receptor ligand
  • the other drug particularly ⁇ 3PUFAs
  • both drugs are administered, and the administration of one drug is stopped when the effect starts to appear or when the effect is fully manifested.
  • the dose of the drug may be decreased in stages.
  • the dose and duration of ⁇ 3PUFAs used in the preventive / ameliorating or treating agent for CB receptor-related diseases of the present invention and the preventive or alleviating side effect due to CB receptor ligand are sufficient to exhibit the intended effect and although it is a period, it can be appropriately increased or decreased depending on its dosage form, administration method, number of administrations per day, symptoms and degree of side effects, body weight, age and the like.
  • EPA-E and / or DHA-E is 0.1 to 10 g / day, preferably 0.3 to 6 g / day, more preferably 0.6 to 4 g / day, still more preferably 0.9 to 2.7 g / day is administered in 1 to 3 divided doses, but the entire dose may be administered in one or several divided doses as necessary.
  • the administration time is preferably during or after meals, more preferably immediately after meals (within 30 minutes).
  • it can be administered as an oral liquid preparation such as an emulsion or a bile acid-added preparation without any restriction on the time of medication.
  • the administration period is appropriately determined depending on the degree of symptoms and the degree of improvement, and is not limited, but for example, 1 year or more, preferably 2 years or more, more preferably 3.5 years or more. More preferably, for more than 5 years, the onset and / or recurrence of the CB receptor-related disease is continued while the pathology or biochemical index of the CB receptor-related disease and the side effects due to the CB receptor ligand continue. It is desirable to continue administration while the state of high risk continues and during the state of high risk of side effects and / or recurrence due to CB receptor ligand. Further, for example, it may be administered every other day or administered for 2 to 3 days per week, and in some cases, a drug holiday of about 1 to 3 months, preferably about 1 week to 1 month may be provided. it can.
  • the agent for preventing / ameliorating or treating a CB receptor-related disease of the present invention and the agent for preventing or alleviating side effects caused by a CB receptor ligand include an active ingredient, a compound alone (including other ingredients inevitably contained during purification). In some cases) or suitable commonly used carriers, media, excipients, binders, lubricants, coloring agents, flavoring agents, emulsifying agents, suspending agents (eg Tween 80).
  • Gum arabic solution Gum arabic solution
  • absorption enhancers eg bile acids such as ursodeoxycholic acid
  • isotonic agents pH adjusters, stabilizers, soothing agents, flavoring agents, flavoring agents, preservatives, antiseptics
  • oxidizing agents eg glycerin, propylene glycol
  • solubilizers eg glycerin, propylene glycol
  • additives include lactose, partially pregelatinized starch, hydroxypropylcellulose, macrogol, tocopherol, hydrogenated oil, sucrose fatty acid ester, hydroxypropylmethylcellulose, titanium oxide, talc, dimethylpolysiloxane, silicon dioxide, and / or carnauba wax. Etc. may be contained.
  • ⁇ 3PUFAs are highly unsaturated, so it is desirable to contain an effective amount of an antioxidant.
  • an antioxidant for example, at least one selected from oil-soluble antioxidants such as butylated hydroxytoluene, brechated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and ⁇ -tocopherol is used as an antioxidant. It is desirable to contain an effective amount.
  • oil-soluble antioxidants such as butylated hydroxytoluene, brechated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and ⁇ -tocopherol is used as an antioxidant. It is desirable to contain an effective amount.
  • a water-soluble antioxidant and an oil-soluble antioxidant such as ascorbic acid and derivatives thereof, erythorbic acid, nitrite, and citric acid.
  • the dosage form of the preparation is not particularly limited, and may be an oral preparation or a parenteral preparation.
  • oral preparation for example, oral liquid preparations such as tablets, film-coated tablets, capsules, microcapsules, granules, fine granules, powders, emulsions, syrups, jellies, or inhalants are preferable.
  • Parenteral preparations include, for example, ointments, suppositories, injections (emulsification, suspension, non-aqueous), solid injections used when emulsified or suspended, infusion preparations, or transdermal absorption.
  • An external preparation such as an agent is preferred.
  • Oral preparations can be administered to patients by oral administration, and parenteral preparations can be administered to patients intravenously or intraarterially, by inhalation, rectal, vaginal or external.
  • oral administration in capsules such as soft capsules or microcapsules, or in tablets, film-coated tablets, and emulsions is particularly preferable.
  • it may be orally administered as an enteric preparation or sustained-release preparation, and is preferably administered orally as a jelly agent to dialysis patients or patients who have difficulty swallowing.
  • oral administration as an oral liquid preparation such as an emulsion is preferable because absorption of ⁇ 3PUFAs and / or CB receptor ligand is promoted, administration can be performed without any restriction on the dose, and the dose of the drug can be reduced.
  • the emulsion particles have a smaller diameter, preferably an average diameter of 5 ⁇ m or less, more preferably 1 ⁇ m or less, still more preferably 0.5 ⁇ m or less, and still more preferably 0.2 ⁇ m or less.
  • any emulsifier can be used as long as it can be used in pharmaceutical preparations.
  • examples include polyglycerin fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, sorbitan monostearate, sorbitan trioleate, sodium lauryl sulfate, and nonionic surfactant, preferably egg yolk lecithin, soybean lecithin , Polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, sorbitan fatty acid ester and propylene glycol fat Esters il
  • an emulsification aid such as fatty acids having 12 to 22 carbon atoms such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid and myristic acid, or salts thereof.
  • the stabilizer include phosphatidic acid, ascorbic acid, glycerin, cetanol, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like.
  • Surfactants include sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, Examples include polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene polyoxypropylene alkyl ether.
  • Antioxidants include butyrated hydroxytoluene, breached hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin and ⁇ -tocopherol, as well as ascorbic acid and its derivatives
  • Water-soluble antioxidants such as erythorbic acid, nitrite and citric acid are exemplified.
  • the content of EPA in the emulsion is preferably 1 to 60% by mass, more preferably 3 to 40% by mass, and further preferably 5 to 30% by mass.
  • the content of the emulsifier is preferably 0.1 to 10% by mass, more preferably 0.2 to 5% by mass, and still more preferably 0.5 to 3% by mass.
  • the emulsion of the present invention is mixed with, for example, an active ingredient, an emulsifier, glycerin, purified water, and other additives such as an antioxidant, if necessary, and heated to form a solution, which is a normal homogenizer, such as a Manton Gorin type homogenizer.
  • a normal homogenizer such as a Manton Gorin type homogenizer.
  • emulsification is preferably performed at a pressure of 50 to 700 kg / cm 2 , preferably about 1 to 50 times, more preferably about 2 to 20 times, or a microfluidizer, a thin film It can be produced by homogenization using a swirl type high-speed mixer, a high-pressure jet flow reversal type emulsifier, an ultrasonic homogenizer, or the like. Prior to this, preliminary emulsification may be performed using a homomixer or the like.
  • EPA-E group received 1000 mg / kg EPA-E, rimonabant group 10 mg / kg rimonabant and the combination group EPA-E 1000 mg / kg and rimonabant 10 mg / kg 5% Arabic It was suspended in an aqueous rubber solution using Hiscotron (Microtech Nithion) and orally administered once a day.
  • the control group was orally administered with a 5% gum arabic aqueous solution once a day.
  • the body weight was measured every day during the breeding period, and the food intake on the last day of the breeding was measured.
  • the amount of food consumed on the last day of breeding in each group and the mean value ⁇ standard error of weight gain during the breeding period were calculated, and Student's t test was performed.
  • EPA-E had no effect on food intake or weight gain when administered alone orally. And nevertheless, when EPA-E is orally administered in combination with rimonabant (combination group), feeding inhibition and mainly via central CB1 receptor over-suppression by rimonabant, a CB1 receptor inverse agonist, and All the suppression of weight gain was restored.
  • rimonabant combination group
  • the EPA glyceride produced by oral administration of EPA-E exhibits a neutral antagonist-like action on the CB1 receptor, and through this neutral antagonist-like action, suppresses excessive inhibition of the CB1 receptor, thereby suppressing feeding and body weight. It is thought that the increase suppression was restored.
  • the preventive / improving or therapeutic agent of the present invention over- or over-suppressed the CB1 receptor. It is useful for the prevention / amelioration or treatment of CB1 receptor-related diseases caused by this.
  • the preventive or alleviating agent for side effects of the present invention is useful for preventing or reducing side effects caused by a CB1 receptor agonist, antagonist or inverse agonist.
  • the preventive / improving or treating agent and the side effect preventing or reducing agent of the present invention do not act on the CB1 receptor in a state where the CB1 receptor is not excessively enhanced or excessively suppressed, there is an advantage that no side effect is exhibited.
  • the prevention / improvement or therapeutic effect of CB1 receptor-related diseases caused by excessive enhancement or excessive suppression of the CB1 receptor of the present invention can be evaluated by the following animal model test or clinical model test.
  • mice in each group are set: a control group, an EPA-E100 group (administered with EPA-E 100 mg / kg), and an EPA-E300 group (administered with EPA-E 300 mg / kg).
  • EPA-E is suspended in a 5% gum arabic aqueous solution using hiscotron and administered orally once a day during the breeding period.
  • the control group is orally administered with a 5% gum arabic aqueous solution once a day.
  • Administration of nicotine and the following conditions are performed from 3 weeks after the breeding.
  • a 121.4 mg / ml nicotine aqueous solution was prepared and injected into an osmotic pump (Alzet 2001 mini-osmotic pump (1 ⁇ l / hour for 7 days)) implanted subcutaneously in the back of the rat, and 10 mg / kg / day.
  • an osmotic pump Alzet 2001 mini-osmotic pump (1 ⁇ l / hour for 7 days) implanted subcutaneously in the back of the rat, and 10 mg / kg / day.
  • nicotine receptor antagonist mecalamine (1 mg / ml) or physiological saline solution was administered subcutaneously and placed in one compartment for 60 minutes, and the opposite of the morning treatment (morning in the morning) Conditioning is performed by the counterbalance method, in which physiological saline is administered to rats administered with mecalamine, and mecalamine is administered to rats administered with physiological saline) and placed in the other compartment for 60 minutes.
  • EPA-E administration is expected to reduce the time withdrawn from the compartment conditioned by subcutaneous administration of mecalamine in a dose-dependent manner and suppress the mecalamine-induced aversive effect.
  • the EPA-E group is expected to have a higher rate of disappearance of phantom limbs and phantom limb pain and a lower incidence than the control group.
  • a hiccup-like reaction is induced by mechanically stimulating the nasopharyngeal head behind the uvula with a cotton swab through this tube.
  • Hiccup-like reaction is confirmed by electrical muscle contraction with electrodes placed on the posterior cricoid cartilage and diaphragm of the larynx.
  • the intracapsular pressure during the hiccup-like reaction is measured with a pressure transducer via a latex balloon placed at 2/3 of the esophagus.
  • the intracapsular pressure at the time of hiccup-like reflexes by 10 stimuli is summed to give the intensity of hiccup-like reflexes (Oshima T., Anthesia and Analgesia, 2004, Vol. 98, 346-352).
  • a compounding agent with EPA-E and a CB receptor ligand is produced.
  • This is emulsified by passing 10 times under a pressure of 120 kg / cm 2 in the first stage and a total pressure of 500 kg / cm 2 using a Manton Gorin type homogenizer. Thereby, an emulsion having an average particle size of 0.2 ⁇ m or less is obtained. 30 ml of this emulsion is dispensed into ampoules to obtain an emulsion containing 1.8 g of EPA-E and 20 mg of rimonabant per ampoule.
  • an emulsion having an average particle diameter of 1 ⁇ m or less is obtained.
  • 40 ml of this emulsion is dispensed into glass bottles to obtain an emulsion containing about 3.36 g as EPA-E + DHA-E and 4 mg as dronabinol per bottle.
  • the prophylactic / ameliorating or treating agent for CB receptor-related diseases of the present invention containing at least one selected from the group consisting of ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient is highly safe, It is expected to show a preventive / improving or therapeutic effect on a syndrome, disorder or disease caused by excessive enhancement and excessive suppression of the CB receptor, particularly the CB1 receptor. In particular, it is expected that patients who exhibit postoperative cognitive decline, nicotine addiction, refractory hiccups, tic disorders or abnormal taste (taste) will have a preventive / improving or therapeutic effect.
  • the preventive or alleviating side effect of a CB receptor ligand containing at least one selected from the group consisting of ⁇ 3PUFAs and pharmaceutically acceptable salts and esters thereof as an active ingredient of the present invention is highly safe and effective. It is expected to exhibit an effect of preventing or reducing side effects caused by administration of a CB receptor ligand, particularly a CB1 receptor antagonist or inverse agonist. In particular, it is expected to show a preventive or alleviating effect on nausea, mood swings associated with depressive symptoms, anxiety, immobility dizziness, suicide attempts, eating disorders, memory disorders or drug dependence.
  • CB receptor ligands can be reduced by the present invention, and treatment can be continued in patients who have failed to administer CB receptor ligands due to these side effects or who have had to be interrupted. it can.

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Abstract

La présente invention concerne un agent prophylactique/d'amélioration ou thérapeutique destiné aux maladies associées au récepteur des CB,lequel comprenant au moins un membre choisi dans le groupe constitué de ?3PUFA et de leurs sels et esters pharmaceutiquement acceptables en tant que principe actif. L'invention a également pour objet l'agent prophylactique/ d'amélioration ou thérapeutique. Il est ainsi devenu possible de fournir un agent prophylactique/d'amélioration ou thérapeutique sans risque et hautement efficace pour les maladies associées au récepteur des CB ainsi qu'un procédé d'utilisation de cet agent prophylactique/d'amélioration ou thérapeutique.
PCT/JP2009/064292 2008-08-13 2009-08-13 Agent prophylactique/d’amélioration ou thérapeutique destiné aux maladies associées au récepteur des cannabinoïdes WO2010018856A1 (fr)

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KR20160093729A (ko) * 2013-12-19 2016-08-08 타소스 지오지우 신경계 손상을 수반하는 질병을 치료하기 위한 오메가 3 지방산 조성물
WO2018112138A1 (fr) * 2016-12-15 2018-06-21 Anavi Goffer Sharon Traitement de troubles mentaux, du mouvement et du comportement
WO2020257333A1 (fr) * 2019-06-18 2020-12-24 Opiant Pharmaceuticals, Inc. Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes
US11471437B2 (en) 2019-06-18 2022-10-18 Opiant Pharmaceuticals, Inc. Compositions and methods for treating cannabinoid hyperemesis syndrome with a cannabinoid receptor antagonist

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160093729A (ko) * 2013-12-19 2016-08-08 타소스 지오지우 신경계 손상을 수반하는 질병을 치료하기 위한 오메가 3 지방산 조성물
JP2017501169A (ja) * 2013-12-19 2017-01-12 ゲオルギウ，タッソス 神経系に対する損傷に関与する疾病を治療するためのオメガ３脂肪酸の組成物
KR101898358B1 (ko) * 2013-12-19 2018-09-12 타소스 지오지우 신경계 손상을 수반하는 질병을 치료하기 위한 오메가 3 지방산 조성물
WO2018112138A1 (fr) * 2016-12-15 2018-06-21 Anavi Goffer Sharon Traitement de troubles mentaux, du mouvement et du comportement
WO2020257333A1 (fr) * 2019-06-18 2020-12-24 Opiant Pharmaceuticals, Inc. Compositions et méthodes de traitement du surdosage aigu aux cannabinoïdes avec un antagoniste des récepteurs cannabinoïdes
US11471437B2 (en) 2019-06-18 2022-10-18 Opiant Pharmaceuticals, Inc. Compositions and methods for treating cannabinoid hyperemesis syndrome with a cannabinoid receptor antagonist

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