WO1994018965A1 - Therapeutic use of pyridoxine pyrrolidone carboxylate - Google Patents
Therapeutic use of pyridoxine pyrrolidone carboxylate Download PDFInfo
- Publication number
- WO1994018965A1 WO1994018965A1 PCT/EP1994/000518 EP9400518W WO9418965A1 WO 1994018965 A1 WO1994018965 A1 WO 1994018965A1 EP 9400518 W EP9400518 W EP 9400518W WO 9418965 A1 WO9418965 A1 WO 9418965A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyridoxine
- pyrrolidone carboxylate
- oxo
- day
- ethanol
- Prior art date
Links
- MQNRNEABTODWHK-UHFFFAOYSA-N [5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]methyl 2-oxopyrrolidine-1-carboxylate Chemical compound OCC1=C(O)C(C)=NC=C1COC(=O)N1C(=O)CCC1 MQNRNEABTODWHK-UHFFFAOYSA-N 0.000 title abstract description 7
- 230000001225 therapeutic effect Effects 0.000 title description 7
- 235000021588 free fatty acids Nutrition 0.000 claims abstract description 12
- 238000009825 accumulation Methods 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 125000004494 ethyl ester group Chemical group 0.000 claims abstract description 6
- 230000004075 alteration Effects 0.000 claims abstract description 3
- 230000009088 enzymatic function Effects 0.000 claims abstract description 3
- 238000011282 treatment Methods 0.000 claims description 8
- UNNBZWSRXVKJAA-UHFFFAOYSA-N O=C1CCC(N1)=O.N1=C(C)C(O)=C(CO)C(CO)=C1 Chemical compound O=C1CCC(N1)=O.N1=C(C)C(O)=C(CO)C(CO)=C1 UNNBZWSRXVKJAA-UHFFFAOYSA-N 0.000 claims description 7
- 229940071139 pyrrolidone carboxylate Drugs 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000007863 steatosis Effects 0.000 claims description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 8
- 210000001557 animal structure Anatomy 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
- 235000019441 ethanol Nutrition 0.000 description 21
- 230000000694 effects Effects 0.000 description 12
- 210000004185 liver Anatomy 0.000 description 12
- 210000004556 brain Anatomy 0.000 description 11
- 210000002216 heart Anatomy 0.000 description 11
- 210000003734 kidney Anatomy 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 8
- 230000035508 accumulation Effects 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- ZQRPGFWGRMBUQW-QLAMLYEZSA-N (2s)-2-amino-5-[[(2r)-3-[[(2r)-2-[[(4s)-4-amino-4-carboxybutanoyl]amino]-3-(carboxymethylamino)-3-oxopropyl]disulfanyl]-1-(carboxymethylamino)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid;(2s)-2-amino-5-[[(2r)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan- Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O.OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O ZQRPGFWGRMBUQW-QLAMLYEZSA-N 0.000 description 3
- 206010001605 Alcohol poisoning Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- CQYYGCVORGQMEQ-UHFFFAOYSA-N 2,5-dioxopyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1C(=O)CCC1=O CQYYGCVORGQMEQ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 2
- 235000008160 pyridoxine Nutrition 0.000 description 2
- 239000011677 pyridoxine Substances 0.000 description 2
- 229940011671 vitamin b6 Drugs 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-M Arachidonate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O YZXBAPSDXZZRGB-DOFZRALJSA-M 0.000 description 1
- 108010053070 Glutathione Disulfide Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- COBTXXJDGCSXLA-UHFFFAOYSA-N N1C=CC=C1.N1=C(C)C(O)=C(CO)C(CO)=C1 Chemical compound N1C=CC=C1.N1=C(C)C(O)=C(CO)C(CO)=C1 COBTXXJDGCSXLA-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229940114078 arachidonate Drugs 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-M linolenate Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC([O-])=O DTOSIQBPPRVQHS-PDBXOOCHSA-M 0.000 description 1
- 229940040452 linolenate Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000001173 tumoral effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
Definitions
- the present invention has as the object to provide a new therapeutic use of a known drug, namely pyridoxine 5-oxo-2-pyrrolidone carboxylate, also known as 5-hydroxy-6-methyl-3,4-pyridinemethanol 5-oxo-2-pyrrolidone carboxylate of the formula:
- Pyridoxine known also under the name of B6 vitamin, finds several therapeutic uses, among which the treatment of acute alcoholic intoxication states has been proposed in the past. However, this therapeutic indication has been subsequently abandoned, since it did not receive experimental confirmation.
- the compound of the present invention finds also application in treating acute alcoholic intoxication caused by ethyl alcohol (Italian Patent No.
- the object of this invention is a novel therapeutic use of the same compound, i.e. pyridoxine 5-oxo-2-pyrrolidone carboxylate.
- Free fatty acids and esters thereof have important effects in the human organism and, particularly, several negative or harmful effects, due to their accumulation in tissues, such as heart, brain, kidney, liver and plasma, have been noted.
- liver As far as liver is concerned, for example, they are responsible of the so-called steatosis.
- the ethyl esters of free fatty acids are, in turn, one of the main metabolites of the acids themselves and tend to accumulate in concentrations that might reach levels up to 100 micromoles in the myocardium, with a half life of nearly 16 hrs. This means that they persist at tissue level even after the factors promoting these accumulations are eliminated, as, for example, the ethyl alcohol action.
- the free fatty acids esterification represents a vehicle of toxic states.
- 5-oxo-2-pyrrolidone carboxylate as active principle for inhibiting the free fatty acid ethyl esters, the therapeutic treatment including the active principle administration in oral dosages from 250 mg/day to 2500 mg/day, and in parenteral dosages from 250 mg/day to 1500 mg/day.
- Wistar rats of 250-300 g weight have been randomly divided in groups of six animals each.
- the first group of animals was orally administered with a 20% ethanol solution at a
- the second group was administered as the first group, except that each day, for all the seven days of the parenteral treatment, received 60 mg/kg of pyridoxine pyrrolidone carboxylate in crystalline form, 30 minutes before the ethanol solution was administered.
- the third group was used as a control group and was administered with a physiological solution.
- Tables 1 and 2 report the measuring data of fatty acid ethyl ester, obtained in vivo. in the heart, plasma, liver, kidney and brain, respectively.
- the heart is the organ showing the highest levels of ethyl esters (6.96 nmoles of total esters/mg of proteins).
- Stearate, linoleate, linolenate and arachidonate are the mostly present chemical species of ethanol esterified fatty acids.
- the analyzed organs showed the following sequence: heart - kidney - brain - plasma - liver
- the treatment with the active principle of the invention produces a significant reduction of the contents of total esters formed, particularly in the kidney, brain, heart and plasma (80-60%).
- Table 3 shows the effect of ethanol solution administration on the
- the activity of this enzyme appears to be strengthened by the ethanol administration in the liver, kidney, heart and, particularly, in the • brain
- DCNB-GSH TRASFERASE nmoles / min / mg protein
- Table 4 illustrates the effect of the ethanol administration on the activity decrease of the GSH reductase, which occurs in all tested organs, except for brain, where it is found to be strengthened.
- the administration of this active principle by the normal administration means and known dosages for normal uses is to be suggested, when the free fatty acid ester formation, accumulation of the acids themselves and alteration of enzymatic functions bound to said free fatty acid action, such as GSH-S-transferase and GSH-reductase, must be controlled and compensated for.
- the preparation of the pharmaceutical compositions using the active principle of this invention and dosages thereof reference is made to the already known pharmaceutical compositions for the control and therapy of acute alcoholic intoxication.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI93A000341 | 1993-02-23 | ||
| ITMI930341A IT1263957B (it) | 1993-02-23 | 1993-02-23 | Impiego terapeutico del pirrolidon carbossilato di piridossina |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994018965A1 true WO1994018965A1 (en) | 1994-09-01 |
Family
ID=11365120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1994/000518 WO1994018965A1 (en) | 1993-02-23 | 1994-02-19 | Therapeutic use of pyridoxine pyrrolidone carboxylate |
Country Status (3)
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043259A (en) * | 1998-07-09 | 2000-03-28 | Medicure Inc. | Treatment of cardiovascular and related pathologies |
| US6339085B1 (en) | 1999-03-08 | 2002-01-15 | The University Of Manitoba | Therapeutics for cardiovascular and related diseases |
| US6489345B1 (en) | 1999-07-13 | 2002-12-03 | Medicure, Inc. | Treatment of diabetes and related pathologies |
| US6861439B2 (en) | 2000-03-28 | 2005-03-01 | Medicure International, Inc. | Treatment of cerebrovascular disease |
| US6867215B2 (en) | 2000-02-29 | 2005-03-15 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| US6897228B2 (en) | 2000-07-07 | 2005-05-24 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: new uses |
| US7115625B2 (en) | 1999-08-24 | 2006-10-03 | Medicure International Inc. | Treatment of cardiovascular and related pathologies |
| US7442689B2 (en) | 2000-02-29 | 2008-10-28 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| US7459468B2 (en) | 2004-10-28 | 2008-12-02 | Medicure International, Inc. | Aryl sulfonic pyridoxines as antiplatelet agents |
| WO2009073943A1 (en) * | 2007-12-12 | 2009-06-18 | Iovate T. & P. Inc. | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) |
| US20120277270A1 (en) * | 2007-07-03 | 2012-11-01 | Alcobra Ltd. | Method for Decreasing Symptoms of Alcohol Consumption |
| US8710067B2 (en) | 2009-06-25 | 2014-04-29 | Alcobra Ltd. | Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition |
| US8889715B2 (en) | 2008-07-29 | 2014-11-18 | Alcobra Ltd. | Substituted pyridoxine-lactam carboxylate salts |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2485372A1 (fr) * | 1980-06-30 | 1981-12-31 | Baldacci Lab Spa | Composition pharmaceutique pour le traitement des etats d'intoxication alcoolique aigue a base de 5-oxo-2-pyrrolidone carboxylate de pyridoxine et procede de preparation de ce dernier |
-
1993
- 1993-02-23 IT ITMI930341A patent/IT1263957B/it active IP Right Grant
- 1993-05-22 TW TW082104060A patent/TW230749B/zh not_active IP Right Cessation
-
1994
- 1994-02-19 WO PCT/EP1994/000518 patent/WO1994018965A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2485372A1 (fr) * | 1980-06-30 | 1981-12-31 | Baldacci Lab Spa | Composition pharmaceutique pour le traitement des etats d'intoxication alcoolique aigue a base de 5-oxo-2-pyrrolidone carboxylate de pyridoxine et procede de preparation de ce dernier |
Non-Patent Citations (7)
| Title |
|---|
| A. MANCINELLA: "STEATOSI E FIBROSI: PRIMA TAPPA DEL DANNO EPATICO INDOTTO DALL' ABUSO CRONICO DI ALCOOL", CLIN.THER., vol. 137, no. 1, 15 April 1991 (1991-04-15), pages 29 - 38, XP008114049 * |
| CHEMICAL ABSTRACTS, vol. 118, no. 9, 1 March 1993, Columbus, Ohio, US; abstract no. 76259s, E.F.KONOPLYA ET AL.: "Corrective activity of metadoxil in radiation-induced dyslipoproteinemia" * |
| L.CACCIATORE ET AL.: "METADOXINE PREVENTION OF ALCOHOL-INDUCED FATTY LIVER IN THE RAT", CLIN.TRIALS J., vol. 23, no. 5, 1986, pages 289 - 292 * |
| L.CACCIATORE ET AL.: "METADOXINE TREATMENT OF FATTY LIVER ASSOCIATED WITH CHRONIC HEPATITIS", CLIN.TRIALS J., vol. 25, no. 3, 1988, pages 220 - 226, XP008114048 * |
| L.SERGIACOMO ET AL.: "TRATTAMENTO DELL' EPATOSTEATOSI ALCOOLICA CON METADOXINA", CLIN.TER., vol. 119, no. 2, 31 October 1986 (1986-10-31), pages 133 - 141 * |
| S. MARCHI ET AL.: "LIVER TRIGLYCERIDE ACCUMULATION AFTER CHRONIC ETHANOL ADMINISTRATION: A POSSIBLE PROTECTIVE ROLE OF METADOXINA AND UBIQUINONE", INT.J.TISSUE REACT., vol. 12, no. 4, 1990, pages 247 - 250 * |
| VESTSI AKAD. NAVUK BELARUSI, SER. BIYAL. NAVUK., no. 3-4, 1992, pages 55 - 59 * |
Cited By (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043259A (en) * | 1998-07-09 | 2000-03-28 | Medicure Inc. | Treatment of cardiovascular and related pathologies |
| US6890943B2 (en) | 1999-03-08 | 2005-05-10 | Medicure Inc. | Pyridoxal analogues and methods of treatment |
| US6339085B1 (en) | 1999-03-08 | 2002-01-15 | The University Of Manitoba | Therapeutics for cardiovascular and related diseases |
| US7230009B2 (en) | 1999-03-08 | 2007-06-12 | Medicure, Inc. | Pyridoxal analogues and methods of treatment |
| US6489345B1 (en) | 1999-07-13 | 2002-12-03 | Medicure, Inc. | Treatment of diabetes and related pathologies |
| US7115626B2 (en) | 1999-08-24 | 2006-10-03 | Medicure International Inc. | Treatment of cardiovascular and related pathologies |
| US7115625B2 (en) | 1999-08-24 | 2006-10-03 | Medicure International Inc. | Treatment of cardiovascular and related pathologies |
| US7125889B2 (en) | 1999-08-24 | 2006-10-24 | Medicure International Inc. | Treating of cardiovascular and related pathologies |
| US7132430B2 (en) | 1999-08-24 | 2006-11-07 | Medicure International Inc. | Treatment of cardiovascular and related pathologies |
| US7144892B2 (en) | 1999-08-24 | 2006-12-05 | Merrill Lynch Capital Canada Inc. | Treatment of cardiovascular and related pathologies |
| US7148233B2 (en) | 1999-08-24 | 2006-12-12 | Merrill Lynch Capital Canada Inc. | Treatment of cardiovascular and related pathologies |
| US6867215B2 (en) | 2000-02-29 | 2005-03-15 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| US7105673B2 (en) | 2000-02-29 | 2006-09-12 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| US7442689B2 (en) | 2000-02-29 | 2008-10-28 | Medicure International Inc. | Cardioprotective phosphonates and malonates |
| US6861439B2 (en) | 2000-03-28 | 2005-03-01 | Medicure International, Inc. | Treatment of cerebrovascular disease |
| US6897228B2 (en) | 2000-07-07 | 2005-05-24 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: new uses |
| US7425570B2 (en) | 2000-07-07 | 2008-09-16 | Medicure International Inc. | Pyridoxine and pyridoxal analogues: new uses |
| US7459468B2 (en) | 2004-10-28 | 2008-12-02 | Medicure International, Inc. | Aryl sulfonic pyridoxines as antiplatelet agents |
| US20120277270A1 (en) * | 2007-07-03 | 2012-11-01 | Alcobra Ltd. | Method for Decreasing Symptoms of Alcohol Consumption |
| US8476304B2 (en) * | 2007-07-03 | 2013-07-02 | Alcobra Ltd. | Method for decreasing symptoms of alcohol consumption |
| US9808446B2 (en) | 2007-07-03 | 2017-11-07 | Alcobra Ltd. | Method for decreasing symptoms of alcohol consumption |
| WO2009073943A1 (en) * | 2007-12-12 | 2009-06-18 | Iovate T. & P. Inc. | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) |
| US8889715B2 (en) | 2008-07-29 | 2014-11-18 | Alcobra Ltd. | Substituted pyridoxine-lactam carboxylate salts |
| US9428458B2 (en) | 2008-07-29 | 2016-08-30 | Alcobra Ltd. | Substituted pyridoxine-lactam carboxylate-salts |
| US8710067B2 (en) | 2009-06-25 | 2014-04-29 | Alcobra Ltd. | Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI930341A0 (it) | 1993-02-23 |
| TW230749B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1994-09-21 |
| IT1263957B (it) | 1996-09-05 |
| ITMI930341A1 (it) | 1994-08-23 |
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