CN1276704A - 一种抑制酗酒者的脱瘾综合症和饮酒欲望并预防健康人体滥用酒精的组合物 - Google Patents
一种抑制酗酒者的脱瘾综合症和饮酒欲望并预防健康人体滥用酒精的组合物 Download PDFInfo
- Publication number
- CN1276704A CN1276704A CN98810325A CN98810325A CN1276704A CN 1276704 A CN1276704 A CN 1276704A CN 98810325 A CN98810325 A CN 98810325A CN 98810325 A CN98810325 A CN 98810325A CN 1276704 A CN1276704 A CN 1276704A
- Authority
- CN
- China
- Prior art keywords
- carnitine
- propionyl
- pharmacology
- alcohol
- acetyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 title abstract 2
- 235000019788 craving Nutrition 0.000 title abstract 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 claims abstract description 15
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 claims abstract description 14
- 235000013305 food Nutrition 0.000 claims abstract description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 235000005911 diet Nutrition 0.000 claims description 7
- 229960004203 carnitine Drugs 0.000 claims description 5
- 230000035622 drinking Effects 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 4
- 229940009098 aspartate Drugs 0.000 claims description 4
- 230000037213 diet Effects 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 230000000378 dietary effect Effects 0.000 claims description 3
- 235000001497 healthy food Nutrition 0.000 claims description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 3
- NDVRKEKNSBMTAX-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;phosphoric acid Chemical class OP(O)(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O NDVRKEKNSBMTAX-BTVCFUMJSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- YYRMJZQKEFZXMX-UHFFFAOYSA-N calcium;phosphoric acid Chemical compound [Ca+2].OP(O)(O)=O.OP(O)(O)=O YYRMJZQKEFZXMX-UHFFFAOYSA-N 0.000 claims description 2
- 239000005515 coenzyme Substances 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- JMTCDHVHZSGGJA-UHFFFAOYSA-M potassium hydrogenoxalate Chemical compound [K+].OC(=O)C([O-])=O JMTCDHVHZSGGJA-UHFFFAOYSA-M 0.000 claims description 2
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 2
- 239000002426 superphosphate Substances 0.000 claims description 2
- 239000013589 supplement Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 229940066528 trichloroacetate Drugs 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 239000002417 nutraceutical Substances 0.000 abstract description 2
- 235000021436 nutraceutical agent Nutrition 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 235000015872 dietary supplement Nutrition 0.000 abstract 1
- 235000013402 health food Nutrition 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 28
- 241000700159 Rattus Species 0.000 description 15
- 230000000694 effects Effects 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 206010010904 Convulsion Diseases 0.000 description 5
- 206010044565 Tremor Diseases 0.000 description 5
- 230000036461 convulsion Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 235000013334 alcoholic beverage Nutrition 0.000 description 3
- -1 alkanoyl L-carnitine Chemical compound 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 238000009938 salting Methods 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 2
- 229960004782 chlordiazepoxide Drugs 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 108010080705 Ca(2+) Mg(2+)-ATPase Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010017954 Calcium-Transporting ATPases Proteins 0.000 description 1
- 206010012225 Delirium tremens Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241000053208 Porcellio laevis Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical group 0.000 description 1
- AFYNADDZULBEJA-UHFFFAOYSA-N bicinchoninic acid Chemical compound C1=CC=CC2=NC(C=3C=C(C4=CC=CC=C4N=3)C(=O)O)=CC(C(O)=O)=C21 AFYNADDZULBEJA-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000000122 hyperventilation Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000002248 lipoperoxidative effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 1
- 229960003868 paraldehyde Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000002990 phenothiazines Chemical class 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 206010036067 polydipsia Diseases 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Addiction (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- General Chemical & Material Sciences (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Detergent Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
公开了一种含有L－肉碱、乙酰L－肉碱和丙酰L－肉碱或其药理学可接受的盐的联合组合物,它可以作为抑制酗酒者的脱瘾综合症和饮酒欲望的药物组合物,并可以作为预防基本健康的个体,尤其是年轻人滥用酒精的饮食补充物、健康食品或营养品。
Description
本发明涉及一种由L-肉碱与低级链烷酰基L-肉碱或其药理学可接受的盐组成的用于治疗酒精中毒的联合组合物。此联合组合物抑制脱瘾综合症(如震颤、出汗、反射亢进、恶心、焦虑和惊厥)和对酒精的欲望的用途。
至今所用的治疗酒精中毒的药物均表现出较大的缺点。
通常用于治疗酒精脱瘾综合症的大量药物的药理学作用是相似的。实际上，对于惯用的药物中最有用的一些，酒精已产生了交叉耐受性。SNC抑制剂可能适用于所有治疗脱瘾综合症的病人，虽然并不是所有的人都需要它。
曾在治疗中广泛应用的三聚乙醛，由于其讨厌的气味和一系列使用后突然、莫名其妙的死亡而完全被废弃。
现在很少使用快速作用的巴比妥酸盐(戊巴比妥和司可巴比妥)。
可选择的药物是苯并二氮卓类如氯化二氮卓(Chlorodiazepoxide)和安定。然而它们表现出一个严重的缺点，即酗酒者服用氯化二氮卓(Chlorodiazepoxide)和安定后可能中毒并甚至产生身体的成瘾性和脱瘾综合症。
由于不能控制剧烈的震颤性谵妄并且会降低癫痫发作的阈值，所以不建议使用吩噻嗪类。
最近，围绕双硫仑的治疗用途存在一些争论，这种物质干扰乙醛代谢(醇氧化的中间产物)并产生其蓄积，因此引起毒性症状和严重的不适。服用双硫仑12小时内饮酒在5-15分钟内产生面部潮红，随后伴以面部和颈部强烈的血管舒张，并且结膜混浊、搏动性头痛、心动过速、呼吸过度和出汗。在30-60分钟内出现恶心和呕吐，并可能会严重到导致血压过高、头晕，有时产生晕厥或虚脱。此反应持续1-3小时。不适的感觉如此强烈以致很少有病人在服用双硫仑时冒险饮酒。有时此药物也引起惊厥、心率失常和心肌梗塞。
肉碱在降低实验动物的脱瘾综合症方面的功效已见报道。
Abu Murad等[英国病理学杂志(Brit.J.Pathol.)58卷第6期，1977年12月]报道对小鼠“在给予乙醇期间的饮食中加入DL-肉碱…显著降低了酒精脱瘾综合症的强度。”
Corbett等(神经药理学，23卷第2B期，269-271页，1984)提出这样的假设：服用肉碱可以“通过阻止酒精诱发的钙/镁ATP酶活性的变化”而抵抗“长时间服用酒精和酒精脱瘾的至少一部分影响……”。
对于乙酰L-肉碱，Tempesta等(国际临床药理学研究杂志X(1/2)101-107，1990)报告了由多通道双盲安慰剂对照研究得出的初步数据，其提示乙酰L-肉碱在降低至少禁酒一个月的长期酗酒者的某些感知性缺陷方面可能有功效。
还未提出和验证其它链烷酰基L-肉碱，尤其是丙酰L-肉碱，在治疗酗酒方面的功效。
现在已经发现一种含有L-肉碱、乙酰L-肉碱、丙酰L-肉碱或其药理学上可接受的盐的联合组合物不仅能够抑制酗酒者的脱瘾综合症(如震颤、出汗、反射亢进、恶心、焦虑和惊厥)和对酒精的欲望，也能作为一种预防手段，有效地用于基本上健康但偶尔非连续地过度摄入酒精饮料的人。
值得注意的是本发明组合物的使用者也可以是实质上健康的个体，尤其是年轻人，虽然在临床上不能将其认定为酒精成瘾者，但他们偶尔也沉溺于过度摄入烈性酒精饮料，由于在一个较短的时间里生活方式发生了深刻的变化，尤其是对于年轻人，这种情况越来越频繁。这种现象会影响家庭生活及社会和个人关系的重要方面，并产生甚而影响社会经济状况的令人担忧的后果。
本发明的联合组合物不仅可以作为药物组合物，也可以作为饮食的补充物、健康食品、医疗食品(medical food)或营养品(nutraceutical)或作为上述产品中的成分使用。那么，所述组合物除含有L-肉碱和上述链烷酰基L-肉碱的混合物外，也可以含有其它活性成分，如饮食补充物、维生素、辅酶、矿物质等。
L-肉碱/乙酰L-肉碱/丙酰L-肉碱或其药理学可接受的盐的摩尔比为6∶4∶1至3∶2∶1。优选此比例为5∶4∶1。
在单位剂量的剂型中，此组合物含有0.44-0.66g L-肉碱内盐；0.44-0.66g乙酰L-肉碱内盐；和0.12-0.18g丙酰L-肉碱内盐或等摩尔的其药理学可以接受的盐。
L-肉碱、乙酰L-肉碱和丙酰L-肉碱的药理学可接受的盐指这些活性成分与不具有有害毒性或副作用的酸形成的任意一种盐。这些酸是药学专家熟知的。
适宜的盐的非限定性的例子如下：氯化物、溴化物、碘化物、天冬氨酸盐，尤其是酸性天冬氨酸盐；柠檬酸盐，尤其是酸性柠檬酸盐；酒石酸盐；磷酸盐，尤其是酸性磷酸盐；富马酸盐，尤其是酸性富马酸盐；甘油磷酸盐；葡萄糖磷酸盐；乳酸盐；马来酸盐，尤其是酸性马来酸盐；乳清酸盐；草酸盐，尤其是酸性草酸盐；硫酸盐，尤其是酸性硫酸盐；三氯乙酸盐；三氟乙酸盐和甲磺酸盐。
国际药理学杂志33(1986)，201-217列出了FDA批准的药理学可接受的盐，将此出版物结合于此作为参考。
由于L-肉碱及上述链烷酰基L-肉碱几乎是无毒的，因此本发明的联合组合物不引起任何上述提及的有害的毒性或副作用。
以下报告的是一些将本发明的联合组合物与分别服用L-肉碱及乙酰L-肉碱的活性进行比较的体内药理学研究的详细资料。
在下文中，“COMP”代表联合组合物，“LC”代表L-肉碱，“ALC”代表乙酰L-肉碱，“PLC”代表丙酰L-肉碱。
按照Vogel试验法测定的COMP对乙醇依赖性大鼠的镇静作用
使用Wistar雄性大鼠(每笼5只分组)，将其置于21℃连续的亮-暗变换的条件下，喂以标准的实验室饲料。长期给这些动物没有限制地服用10％乙醇达6个月。
使用Keppler D.等在实验分子病理学(Exp.Mol.Path.)9，279(1968)记载的一种Vogel试验的修改方案，测定COMP是否对在寻找乙醇的强迫性行为中包括的焦虑因素具有活性及其强度。
试验开始前，动物禁水48小时。乙醇处置停止时，将动物分为4组，腹膜内给药：第一组(A)接受盐溶液(15ml/kg)，第二组(B)接受COMP(20mg LC+20mg ALC+4mg PLC/kg)，第三组(C)接受LC(20mg/kg)，第四组(D)接受ALC(20mg/kg)。
试验当天，给动物2个饮水瓶，一只盛水，另一只盛水和乙醇的混合物(90∶10v/v)，后一饮水瓶的金属喷嘴与电源相连，动物每舔饮水瓶5次后，传送电击(1mA)10分钟，迫使动物退缩，克服其饮用水-乙醇溶液的欲望。动物拒绝饮用水-乙醇溶液，将它们的注意力仅限于只盛水的饮水瓶，作为有效的指标。将10分钟测定周期内治疗组动物舔瓶的次数与对照组比较，从而对结果进行评定。结果示于表1。
表1
治疗组动物在10分钟测定周期内的舔瓶次数
| 动物组 | 舔瓶次数 |
| A(盐水)B(COMP)C(LC)D(ALC) | 39.8±7.54.9±1.14*10±6.4*32.2±6.4 |
*相比于A，P＜0.01 相比于B，P＜0.05
用Hunt-Maichrowicz法测定COMP对大鼠脱瘾综合症的影响使用每笼5只分组的Wistar雄性大鼠，将其置于21℃连续亮-暗变换的条件下，喂以标准的实验室饲料，进行实验。长期给这些动物没有限制地服用10％乙醇达6个月。
停止给动物服用乙醇8小时后，将动物分为4组，每组5只大鼠。
第一组(A)接受盐溶液(15ml/kg)腹膜内给药，第二组(B)接受COMP(20mg LC+20mg ALC+4mg PLC/kg)，也是腹膜内给药，第三组(C)接受LC(20mg/kg)，第四组(D)给以ALC(20mg/kg)。测定大鼠的震颤，以评价上述治疗酒精脱瘾综合症产生的效果，如同在人体，震颤是脱瘾综合症最具特征性的信号。用Hunt和Majchrowicz描述的方法测定震颤的次数[见Hunt W.A.和Majchrowicz E.，药理学与实验治疗学杂志，213，9-12(1980)]。结果见表2。
表2
| 动物组 | 30分钟 | 60分钟 | 90分钟 | 120分钟 |
| A(盐水)B(COMP)C(LC)D(ALC) | 6±1.50±0.252±0.54±2 | 9±2.50±01±0.55±2 | 8±2.50±0.652±15±1.5 | 9±1.50±0.253±16±2 |
通过观察长期用酒精处理的大鼠受到声音刺激后的行为测定COMP对大鼠脱瘾综合症的影响
使用每笼5只分组的Wistar雄性大鼠，将其置于21℃连续亮-暗变换的条件下，喂以标准的实验室饲料，进行实验。长期给这些动物没有限制地服用10％乙醇达6个月。
停止给动物服用乙醇8小时后，将动物分为4组，每组10只大鼠。
第一组(A)通过腹膜内给药服用盐溶液(15ml/kg)，第二组(B)接受COMP(20mg LC+20mg ALC+4mg PLC/kg)，也是腹膜内给药，第三组(C)接受LC(20mg/kg)，第四组(D)接受ALC(20mg/kg)。观察由一只电铃(100dB)发出声音1分钟而导致大鼠产生行为反应(惊厥)的敏感度，从而评价各种治疗方法对酒精脱瘾综合症的影响。在各组大鼠用药1小时后进行该试验，结果示于表3。
表3
| 动物分组 | 惊厥动物/治疗动物总数 |
| A(盐水)B(COMP)C(LC)D(ALC) | 8/101/105/106/10 |
COMP对长期接受乙醇处理的大鼠的中枢神经系统(CNS)中脂过氧化作用(lipoperoxidation)的影响
进行本研究以测定在服用COMP后丙醛(malonaldehyde，MDA)发生何种变化，MDA是一种表示由于乙醇的有害影响而使中枢神经系统对于自由基伤害的易受损性的可靠而可定量的指标。
试验使用每笼5只分组的Wistar雄性大鼠，将其置于21℃连续亮-暗变换的条件下，喂以标准的实验室饲料。两组大鼠，每组5只，在试验的过程中始终给予10％的乙醇水溶液。第3组动物给予标准的实验室饲料而不接受任何治疗。经过乙醇两个月的处理后，给第一组动物以单次腹膜内注射的剂量服用COMP(20mg LC+20mgALC+4mg PLC/kg)。服药后几小时，将动物处死，迅速取出大脑。用Slater和Sawyer(Slater T.F.和Sawyer B.C.，1971，生物化学杂志，东京8：2180)描述的改良的微量法测定MDA。将组织在0℃于Tris-HCl 0.05M(pH7.4)缓冲液中保持10分钟，然后匀浆。用20％(w/v)三氯醋酸提取部分(0.05ml)脑组织匀浆物。离心后，将0.9ml上清液加到于0.026M Tris-HCl(pH7.0)缓冲液中的0.67％硫代巴比妥酸溶液1ml中。样品置于沸水中10分钟，冷却后用分光光度计测定在532nm的吸光度。以nmol/mg蛋白质表示MDA。用Smith法(Smith等，1985，分析生物化学27：502)，用二辛可宁酸(bicinchoninic acid)作为试剂测定蛋白质。以下的表4显示了MDA在对照组动物、服用乙醇后的动物和服用乙醇+COMP的动物体内的含量。
表4
| 动物分组 | MDAnmol/mg蛋白质 |
| 对照组乙醇组乙醇+COMP | 0.543±0.191.12±0.130.385±0.15 |
本发明的组合物可以用按本领域技术人员已知的常规方法制备成的任何一种常规剂型口服或胃肠外给药。这些剂型包括口服单位剂量的形式，可以为液体或固体，如片剂、胶囊、溶液、糖浆剂等，还可以是可注射的剂型，如小瓶或安瓿装无菌溶液。
这些药物剂型中使用常规的溶剂、稀释剂和赋形剂。可以选择性地加入防腐剂、甜味剂和调味剂。这些物质的非限定性的例子是羧甲基纤维素钠、多山梨醇酯(polysorbate)、山梨醇、微晶淀粉、滑石和其它对于制药技术人员显而易见的物质。
Claims (12)
1.一种可口服或胃肠外给药的组合物，其中含有L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其药理学可接受的盐的混合物。
2.根据权利要求1所述的组合物，其作为抑制酗酒者的脱瘾综合症和饮酒欲望的药物。
3.根据权利要求1所述的组合物，其作为饮食补充物、健康食品、医疗食品、营养品或其组分用于预防酒精在基本健康的人体中滥用。
4.根据权利要求1、2或3所述的组合物，其中L-肉碱：乙酰L-肉碱∶丙酰L-肉碱或其药理学可接受的盐的摩尔比为6∶4∶1至3∶2∶1。
5.根据权利要求4所述的组合物，其中所述的比例为5∶4∶1。
6.根据权利要求4或5所述的组合物，在其单位剂量剂型中含有0.44-0.66g L-肉碱内盐；0.12-0.18g丙酰L-肉碱内盐，或者等摩尔量的其药理学可接受的盐。
7.根据上述任一权利要求所述的组合物，其中L-肉碱、乙酰L-肉碱和丙酰L-肉碱的药理学可接受的盐选自以下物质：氯化物；溴化物；碘化物；天冬氨酸盐，尤其是酸性天冬氨酸盐；柠檬酸盐，尤其是酸性柠檬酸盐；酒石酸盐；磷酸盐，尤其是酸性磷酸盐；富马酸盐，尤其是酸性富马酸盐；甘油磷酸盐；葡萄糖磷酸盐；乳酸盐；马来酸盐，尤其是酸性马来酸盐；乳清酸盐；草酸盐，尤其是酸性草酸盐；硫酸盐，尤其是酸性硫酸盐；三氯乙酸盐；三氟乙酸盐和甲磺酸盐。
8.根据上述任一权利要求所述的组合物，其中含有食物补充物、维生素、辅酶和矿物质。
9.L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其药理学可接受的盐的联合制剂在制备用于抑制酗酒者的脱瘾综合症和饮酒欲望的药物方面的应用。
10.L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其药理学可接受的盐的联合制剂在制备用于预防基本健康个体滥用酒精的健康食品、医疗食品或营养品方面的应用。
11.根据权利要求9或10的用途，其中L-肉碱：乙酰L-肉碱：丙酰L-肉碱或其药理学可接受的盐的摩尔比为6∶4∶1至3∶2∶1。
12.根据权利要求11所述的用途，其中的摩尔比为5∶4∶1。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT97RM000594A IT1295408B1 (it) | 1997-10-03 | 1997-10-03 | Associazione di l-carnitina e alcanoil l-carnitine per il trattamento dell'alcoolismo |
| ITRM97A000594 | 1997-10-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1276704A true CN1276704A (zh) | 2000-12-13 |
| CN1092939C CN1092939C (zh) | 2002-10-23 |
Family
ID=11405277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98810325A Expired - Fee Related CN1092939C (zh) | 1997-10-03 | 1998-09-18 | 一种抑制酗酒者的脱瘾综合症和饮酒欲望并预防健康人体滥用酒精的组合物 |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US6255346B1 (zh) |
| EP (1) | EP1022960B1 (zh) |
| JP (1) | JP2001518484A (zh) |
| KR (2) | KR100530368B1 (zh) |
| CN (1) | CN1092939C (zh) |
| AT (1) | ATE220860T1 (zh) |
| AU (1) | AU730740B2 (zh) |
| BG (1) | BG64363B1 (zh) |
| BR (1) | BR9812604A (zh) |
| CA (1) | CA2305598C (zh) |
| CZ (1) | CZ291801B6 (zh) |
| DE (1) | DE69806788T2 (zh) |
| DK (1) | DK1022960T3 (zh) |
| EA (1) | EA002177B1 (zh) |
| EE (1) | EE04036B1 (zh) |
| ES (1) | ES2180200T3 (zh) |
| HK (1) | HK1028714A1 (zh) |
| HU (1) | HUP0004336A3 (zh) |
| IS (1) | IS2234B (zh) |
| IT (1) | IT1295408B1 (zh) |
| MX (1) | MXPA00003232A (zh) |
| NO (1) | NO20001688L (zh) |
| NZ (1) | NZ503663A (zh) |
| PL (1) | PL189663B1 (zh) |
| PT (1) | PT1022960E (zh) |
| SK (1) | SK283384B6 (zh) |
| UA (1) | UA66807C2 (zh) |
| WO (1) | WO1999017623A1 (zh) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766715B (zh) * | 2008-12-31 | 2012-08-29 | 克科 | 解酒醒酒组合物 |
| CN101766716B (zh) * | 2008-12-31 | 2012-08-29 | 克科 | 解酒醒酒组合物 |
| CN101766637B (zh) * | 2008-12-31 | 2012-08-29 | 克科 | 解酒醒酒组合物 |
| CN101766717B (zh) * | 2008-12-31 | 2012-10-10 | 克科 | 解酒醒酒组合物 |
| CN101766672B (zh) * | 2008-12-31 | 2012-10-10 | 克科 | 解酒醒酒组合物 |
| CN101766635B (zh) * | 2008-12-31 | 2012-10-10 | 克科 | 解酒醒酒组合物 |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6090848A (en) * | 1997-12-01 | 2000-07-18 | Sigma-Tau Healthscience S.P.A. | Compositions and methods for increasing the concentration and/or motility of spermatozoa in humans |
| IT1306179B1 (it) | 1999-07-28 | 2001-05-30 | Sigma Tau Healthscience Spa | Composizione per la prevenzione e cura delle disfunzioni e patologierenali di tipo tossico e funzionale. |
| ITRM20020194A1 (it) | 2002-04-09 | 2003-10-09 | Sigma Tau Healthscience Spa | Composizione utile per aumentare la concentrazione e la motilita' degli spermatozoi e migliorarne la morfologia nell'uomo. |
| US7776913B2 (en) | 2002-12-13 | 2010-08-17 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Carnitines for treating or preventing disorders caused by andropause |
| ITRM20020620A1 (it) * | 2002-12-13 | 2004-06-14 | Sigma Tau Ind Farmaceuti | Uso delle carnitine per la prevenzione e/o il trattamento dei disturbi causati dall'andropausa. |
| CN106176756A (zh) * | 2015-04-30 | 2016-12-07 | 刘力 | 包含手性异构化合物的赖氨酸五维药物组合物及其用途 |
| WO2021211540A1 (en) * | 2020-04-14 | 2021-10-21 | The Regents Of The University Of California | Diagnosis and treatment of addiction |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1245869B (it) * | 1991-06-05 | 1994-10-25 | Sigma Tau Ind Farmaceuti | Impiego di propionil l-carnitina per il recupero del tono muscolare in soggetti immobilizzati |
| DE19527281A1 (de) * | 1995-07-26 | 1997-01-30 | Hans Guenter Berner Gmbh | Nahrungsergänzungsmittel |
| DE69618749D1 (de) * | 1995-12-01 | 2002-03-14 | Unilever Nv | Mikrowellen erhitzbare knusperige Brötchen |
| ATE187329T1 (de) * | 1996-03-04 | 1999-12-15 | Sigma Tau Ind Farmaceuti | Carnitinderivat als arzneimittel zur behandlung von arteriosklerose obliterans |
-
1997
- 1997-10-03 IT IT97RM000594A patent/IT1295408B1/it active IP Right Grant
-
1998
- 1998-09-18 PT PT98946703T patent/PT1022960E/pt unknown
- 1998-09-18 KR KR10-2005-7014865A patent/KR100530368B1/ko not_active IP Right Cessation
- 1998-09-18 EE EEP200000235A patent/EE04036B1/xx not_active IP Right Cessation
- 1998-09-18 US US09/509,652 patent/US6255346B1/en not_active Expired - Fee Related
- 1998-09-18 CN CN98810325A patent/CN1092939C/zh not_active Expired - Fee Related
- 1998-09-18 SK SK476-2000A patent/SK283384B6/sk unknown
- 1998-09-18 ES ES98946703T patent/ES2180200T3/es not_active Expired - Lifetime
- 1998-09-18 WO PCT/IT1998/000249 patent/WO1999017623A1/en active IP Right Grant
- 1998-09-18 AU AU93660/98A patent/AU730740B2/en not_active Ceased
- 1998-09-18 NZ NZ503663A patent/NZ503663A/en unknown
- 1998-09-18 CA CA002305598A patent/CA2305598C/en not_active Expired - Fee Related
- 1998-09-18 PL PL98339621A patent/PL189663B1/pl not_active IP Right Cessation
- 1998-09-18 DK DK98946703T patent/DK1022960T3/da active
- 1998-09-18 MX MXPA00003232A patent/MXPA00003232A/es active IP Right Grant
- 1998-09-18 DE DE69806788T patent/DE69806788T2/de not_active Expired - Fee Related
- 1998-09-18 EP EP98946703A patent/EP1022960B1/en not_active Expired - Lifetime
- 1998-09-18 JP JP2000514534A patent/JP2001518484A/ja active Pending
- 1998-09-18 BR BR9812604-0A patent/BR9812604A/pt not_active Application Discontinuation
- 1998-09-18 KR KR1020007003626A patent/KR100560097B1/ko not_active IP Right Cessation
- 1998-09-18 AT AT98946703T patent/ATE220860T1/de not_active IP Right Cessation
- 1998-09-18 EA EA200000377A patent/EA002177B1/ru not_active IP Right Cessation
- 1998-09-18 HU HU0004336A patent/HUP0004336A3/hu unknown
- 1998-09-18 CZ CZ20001207A patent/CZ291801B6/cs not_active IP Right Cessation
- 1998-09-18 UA UA2000041867A patent/UA66807C2/uk unknown
-
2000
- 2000-03-24 IS IS5416A patent/IS2234B/is unknown
- 2000-03-30 BG BG104286A patent/BG64363B1/bg unknown
- 2000-03-31 NO NO20001688A patent/NO20001688L/no not_active Application Discontinuation
- 2000-10-26 HK HK00106847A patent/HK1028714A1/xx not_active IP Right Cessation
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766715B (zh) * | 2008-12-31 | 2012-08-29 | 克科 | 解酒醒酒组合物 |
| CN101766716B (zh) * | 2008-12-31 | 2012-08-29 | 克科 | 解酒醒酒组合物 |
| CN101766637B (zh) * | 2008-12-31 | 2012-08-29 | 克科 | 解酒醒酒组合物 |
| CN101766717B (zh) * | 2008-12-31 | 2012-10-10 | 克科 | 解酒醒酒组合物 |
| CN101766672B (zh) * | 2008-12-31 | 2012-10-10 | 克科 | 解酒醒酒组合物 |
| CN101766635B (zh) * | 2008-12-31 | 2012-10-10 | 克科 | 解酒醒酒组合物 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1092939C (zh) | 一种抑制酗酒者的脱瘾综合症和饮酒欲望并预防健康人体滥用酒精的组合物 | |
| US9623073B2 (en) | Learning motivation improvers | |
| EP0344704B1 (en) | Use of gamma-hydroxybutyric acid salts for preparing pharmaceutical compositions for use in the treatment of alcoholism, and the compositions obtained | |
| AU2008258958B2 (en) | Anti-fatigue Agents and Oral Compositions Containing Andrographolide as Active Ingredient | |
| US4427694A (en) | Sesamin as a psychotropic agent | |
| JP4166951B2 (ja) | 脳性および加齢性疾患の予防または治療のためのカルニチンおよびレスベラトロールの組み合わせ | |
| JPH07507569A (ja) | ヒトの窒素保持の促進方法 | |
| KR101528381B1 (ko) | 세사민류와 비타민 ｂ１ 류를 배합한 조성물 | |
| EP3789023A1 (en) | Composition for preventing or treating cognitive disorder-associated diseases, containing mumefural | |
| KR20040084168A (ko) | 피니톨 또는 카이로이노시톨을 포함하는 간 질환 예방 및치료용 조성물 | |
| KR20010021694A (ko) | 스트레스 받는 자에 유용한 영양 조성물 | |
| US5708029A (en) | High blood pressure relief method and compositions | |
| JP7026422B1 (ja) | 飲料 | |
| JP2024002801A (ja) | 経口組成物 | |
| EP0616805B1 (en) | Use of acyl L-carnitine gamma-hydroxybutyrate for the treatment of alcoholism | |
| KR20200129120A (ko) | 인지 기능 개선용 조성물 및 불안양 증상 개선용 조성물, 및 뇌 위축 억제용 조성물 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |