AU2002310788A1 - Treatment of dementia and neurodegenerative diseases with intermediate doses of LHRH antagonists - Google Patents
Treatment of dementia and neurodegenerative diseases with intermediate doses of LHRH antagonistsInfo
- Publication number
- AU2002310788A1 AU2002310788A1 AU2002310788A AU2002310788A AU2002310788A1 AU 2002310788 A1 AU2002310788 A1 AU 2002310788A1 AU 2002310788 A AU2002310788 A AU 2002310788A AU 2002310788 A AU2002310788 A AU 2002310788A AU 2002310788 A1 AU2002310788 A1 AU 2002310788A1
- Authority
- AU
- Australia
- Prior art keywords
- use according
- lhrh antagonist
- methyl
- treatment
- monthly
- 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
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 title claims description 20
- 206010012289 Dementia Diseases 0.000 title claims description 6
- 230000004770 neurodegeneration Effects 0.000 title claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 title claims description 6
- 239000002474 gonadorelin antagonist Substances 0.000 claims description 14
- 230000002045 lasting effect Effects 0.000 claims description 4
- 108700008462 cetrorelix Proteins 0.000 claims description 3
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical group C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 claims description 3
- 229960003230 cetrorelix Drugs 0.000 claims description 3
- 239000000816 peptidomimetic Substances 0.000 claims description 3
- NOENHWMKHNSHGX-IZOOSHNJSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-(ca Chemical group C([C@H](C(=O)N[C@H](CCCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 NOENHWMKHNSHGX-IZOOSHNJSA-N 0.000 claims description 2
- 108010023617 abarelix Proteins 0.000 claims description 2
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical group C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 claims description 2
- 229960002184 abarelix Drugs 0.000 claims description 2
- 108010070670 antarelix Proteins 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 108010083551 iturelix Proteins 0.000 claims description 2
- QRYFGTULTGLGHU-NBERXCRTSA-N iturelix Chemical group C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CCCCNC(=O)C=1C=NC=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)CCCNC(=O)C1=CC=CN=C1 QRYFGTULTGLGHU-NBERXCRTSA-N 0.000 claims description 2
- 229950011372 teverelix Drugs 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 235000012208 gluconic acid Nutrition 0.000 description 3
- 239000000174 gluconic acid Substances 0.000 description 3
- 239000003163 gonadal steroid hormone Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 2
- 102000009151 Luteinizing Hormone Human genes 0.000 description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 description 2
- 159000000021 acetate salts Chemical class 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940028334 follicle stimulating hormone Drugs 0.000 description 2
- 229940040129 luteinizing hormone Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Description
Treatment of dementia and neurodegenerative diseases with intermediate doses of LHRH antagonists
The present invention relates to the treatment of dementia and neurodegenerative diseases with intermediate doses of LHRH antagonists which do not cause a castration.
FURUYA, Shuichi et al. in WO 01/78780 teach preventives and remedies for Alzheimer's disesase containing a compound having GnRH antagonism have effects of preventing and treating Alzheimer's disease with little toxicity.
It has been shown in a study by Bowen R.L et al. that serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly higher in individuals suffering of dementia , e.g. Alzheimer's disease. Bowen R.L. et al. propose in their patent application CA 2,309,395 (US priority June 4, 1999, 09/326,180) to lower FSH and LH to minimal levels by the use of castrating doses of analogues of the LH-releasing hormone (LHRH), either super-agonists or antagonists.
This treatment would be accompanied by highly undesirable side effects as lowering sex hormone levels to castration levels would result in loss or reduction of libido, sexual desire and sexual potency. In men and pre-menopausal women this treatment would also result in the typical symptoms of drop of sex hormones like hot flushes, etc. Women would additionally suffer from loss of bone minerals that would limit the treatment. These side effects could be reduced by hormone replacement therapy.
It has been found now that the treatment with intermediate doses of LHRH antagonists results in a sub-maximal lowering of FSH and LH to normal levels that leaves sex hormone levels above the castration treshold. This treatment is highly advantageous as it gives the desired results of normalising FSH and LH levels without the undesirable side-effects of sex hormone blockade. Thus the additional treatment of sex hormone replacement becomes superfluous.
The present invention relates to the treatment of dementia and neurodegenerative diseases with intermediate doses of LHRH antagonists, wherein the antagonist is preferably cetrorelix, teverelix, antide or abarelix. The antagonist can also be the LHRH antagonist D-63 153 (Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle- Arg-Pro-D-Ala-NH2) as described in the PCT application WO 00/55190 A1.
The mentioned LHRH antagonists can also exhibit a heterocyclic skeletal structure. Such peptidomimetics can be for example
- 1 -[7-Chloro-3-(3,5-dimethyl-phenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1 ,2- dihydro-quinolin-6-yl]-3-pyridin-2-yl-urea (described in WO 97/44339),
- 3-[Benzyl-methyl-amino)-methyl]-2-tørf-butyl-8-(2-fluoro-benzyl)-6-(3-methoxy- phenyl)-7-methyl-8H-imidazo[1 ,2-a]pyrimidin-5-one (described in WO 01/29044),
- 2-(2,5-Dimethyl-furan-3-yl)-8-(2-fluoro-benzyl)-3-([methyl-(2-pyridin-2-yl-ethyl)- amino]-methyl)-5-oxo-5,8-dihydro-imidazo[1 ,2-a]pyrimidine-6-carboxylic acid 1- ethyl-propylester (described in WO 00/69859),
- 3-((2-[2-(3,5-Difluoro-phenyl)-1-(2-methoxy-benzoyl)-2-oxo-ethylidene]-2,3- dihydro-1/7-benzoimidazol-5-yl-amino)-methyl)-benzonitrile (described in WO 02/02533).
The LHRH antagonist is given in a monthly dose of 10 to 100 mg per month and the treatment is repeated monthly, two-monthly or lasting several months.
In a preferred embodiment the LHRH antagonist is given in a monthly dose of 30 to 60 mg per month and the treatment is repeated monthly, two-monthly or lasting several months.
Pharmaceutical formulations of the LHRH antagonist suitable for the therapeutic management of dementia and neurodegenerative diseases may be for example
a) acetate salt formulations of the active compounds in the concentration of 1 mg/1 ml or lower where the lyophilisate powder may be dissolved in water for injection or in gluconic acid;
b) acetate salt formulations of the active compounds in the concentration of 1.5 mg/1 ml to 5.0 mg/1 ml, preferably 2.5 mg/1 ml where the lyophilisate powder may be dissolved in water for injection or in gluconic acid;
c) pamoate salt formulations of the active compounds in the concentration of 10 mg/1 ml to 30 mg/1 ml, preferably 15 mg/1 ml where the lyophilisate powder may be dissolved in gluconic acid or in water for injection.
Suitable excipients and dosage forms are for example described by K.H. Bauer, K.-H. Frδmming and C. Fϋhrer, Lehrbuch der Pharmazeutischen Technologie, 6th edition, Stuttgart 1999, pages 163-186 (excipients) and pages 227-386 (dosage forms), including the references as cited therein.
The LHRH antagonist can be administered for example subcutaneous, oral, intramuscular or inhalative.
The disease as mentioned, for example can be treated in accordance with the following scheme.
Example
In one embodiment of the invention a single dose of 30-60 mg of cetrorelix is administered by injection per month. The treatment is continued monthly. In another embodiment the treatment is continued two-mothly or lasting several months after the administration of the single dose.
Claims
1. Use of a LHRH antagonist for the preparation of a medicament for the treatment of dementia and neurodegenerative diseases in humans by administration of intermediate doses, which do not cause a castration.
2. Use according to claim 1 , characterized in that the monthly single dose is in the range of 10 - 100 mg LHRH antagonist.
3. Use according to claims 1 and 2, characterized in that the monthly single dose is about 30 to about 60 mg LHRH antagonist.
4. Use according to one of claims 1 to 3, characterized in that the administration is continued on a monthly or two-monthly or lasting several months base.
5. Use according to one of claims 1 to 4, characterized in that the treated disease is Alzheimer's disease.
6. Use according to one of claims 1 to 5, characterized in that the LHRH antagonist is cetrorelix.
7. Use according to one of claims 1 to 5, characterized in that the LHRH antagonist is teverelix.
8. Use according to one of claims 1 to 5, characterized in that the LHRH antagonist is antide.
9. Use according to one of claims 1 to 5, characterized in that the LHRH antagonist is abarelix.
10. Use according to one of claims 1 to 5, characterized in that the LHRH antagonist is D-63 153 (Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle- Arg-Pro-D-Ala-NH2).
11. Use according to one of claims 1 to 5, characterized in that the LHRH antagonist is a peptidomimetic.
12. Use according to claim 11 in which the peptidomimetic is a compound
- 1 -[7-Chloro-3-(3,5-dimethyl-phenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1 ,2- dihydro-quinolin-6-yl]-3-pyridin-2-yl-urea
- 3-[Benzyl-methyl-amino)-methyl]-2-te/ϊ-butyl-8-(2-fluoro-benzyl)-6-(3- methoxy-phenyl)-7-methyl-8H-imidazo[1,2-a]pyrimidin-5-one
- 2-(2,5-Dimethyl-furan-3-yl)-8-(2-fluoro-benzyl)-3-([methyl-(2-pyridin-2-yl- ethyl)-amino]-methyl)-5-oxo-5,8-dihydro-imidazo[1(2-a]pyrimidine-6- carboxylic acid 1-ethyl-propylester or
- 3-((2-[2-(3,5-Difluoro-phenyl)-1-(2-methoxy-benzoyl)-2-oxo-ethylidene]-2,3- dihydro-1H-benzoimidazol-5-yl-amino)-methyl)-benzonitrile.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28743401P | 2001-04-30 | 2001-04-30 | |
| US60/287,434 | 2001-04-30 | ||
| PCT/EP2002/004677 WO2002102401A1 (en) | 2001-04-30 | 2002-04-27 | Treatment of dementia and neurodegenerative diseases with intermediate doses of lhrh antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2002310788A1 true AU2002310788A1 (en) | 2003-05-15 |
| AU2002310788B2 AU2002310788B2 (en) | 2007-04-05 |
Family
ID=23102886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002310788A Ceased AU2002310788B2 (en) | 2001-04-30 | 2002-04-27 | Treatment of dementia and neurodegenerative diseases with intermediate doses of LHRH antagonists |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US7288517B2 (en) |
| EP (1) | EP1392348B1 (en) |
| JP (1) | JP2004529207A (en) |
| KR (1) | KR20040000446A (en) |
| CN (1) | CN1317030C (en) |
| AT (1) | ATE400287T1 (en) |
| AU (1) | AU2002310788B2 (en) |
| BG (1) | BG108339A (en) |
| BR (1) | BR0209290A (en) |
| CA (1) | CA2444876A1 (en) |
| CZ (1) | CZ20033167A3 (en) |
| DE (1) | DE60227507D1 (en) |
| DK (1) | DK1392348T3 (en) |
| ES (1) | ES2307760T3 (en) |
| HU (1) | HUP0400067A2 (en) |
| IL (1) | IL156777A0 (en) |
| MX (1) | MXPA03008666A (en) |
| NO (1) | NO20034322L (en) |
| NZ (1) | NZ544417A (en) |
| PL (1) | PL362319A1 (en) |
| PT (1) | PT1392348E (en) |
| RU (1) | RU2319501C2 (en) |
| SI (1) | SI1392348T1 (en) |
| SK (1) | SK14512003A3 (en) |
| UA (1) | UA80679C2 (en) |
| WO (1) | WO2002102401A1 (en) |
| ZA (1) | ZA200305326B (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6828415B2 (en) * | 1993-02-19 | 2004-12-07 | Zentaris Gmbh | Oligopeptide lyophilisate, their preparation and use |
| US20020077327A1 (en) * | 1999-09-23 | 2002-06-20 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| EP1300398B1 (en) | 2000-07-05 | 2006-04-05 | Astellas Pharma Inc. | Propane-1,3-dione derivatives |
| DE10137174A1 (en) * | 2001-07-31 | 2003-02-13 | Zentaris Ag | Use of LHRH antagonists in non-castrating doses to improve T cell-mediated immunity |
| US7709519B2 (en) * | 2004-06-04 | 2010-05-04 | Astellas Pharma Inc. | Benzimidazolylidene propane-1,3 dione derivative or salt thereof |
| US20080171736A1 (en) * | 2004-12-23 | 2008-07-17 | Gregory Christopher W | Treatment of Alzheimer's Disease and Mild Cognitive impairment using GnRH-I analogs and one or more of acetylcholinesterase inhibitors and NMDA receptor antagonists |
| CA2590997A1 (en) * | 2004-12-23 | 2006-07-06 | Voyager Pharmaceutical Corporation | Leuprolide acetate and acetylcholinesterase inhibitors or nmda receptor antagonists for the treatment of alzheimer`s disease |
| BRPI0609625A2 (en) | 2005-03-31 | 2010-04-20 | Astellas Pharma Inc | propane-1,3-dione derivatives or salt thereof |
| BRPI0717618A2 (en) | 2006-10-21 | 2013-10-22 | Abbott Gmbh & Co Kg | HYPEROCYCLIC COMPOUNDS AND USE OF THE SAME AS GLYCOGEN SYNTASE KINASE 3 INHIBITORS |
| WO2009043437A2 (en) * | 2007-09-11 | 2009-04-09 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
| EP2187917A2 (en) * | 2007-09-11 | 2010-05-26 | Mondobiotech Laboratories AG | Use of neuropeptide sf, alone or in combination with glp-2, as a therapeutic agent |
| EP2095818A1 (en) * | 2008-02-29 | 2009-09-02 | AEterna Zentaris GmbH | Use of LHRH antagonists at non-castrating doses |
| US20110129532A1 (en) * | 2008-05-29 | 2011-06-02 | Isr Immune System Regulation Ab | Method and means for treating viral disease, in particular hiv/aids |
| CN103119035B (en) | 2010-09-27 | 2015-09-30 | 雅培股份有限两合公司 | Heterogeneous ring compound and they are as the purposes of GSK-3 inhibitor |
| US9090592B2 (en) | 2010-12-30 | 2015-07-28 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
| EP3560555A1 (en) * | 2018-04-26 | 2019-10-30 | LifeArc | A composition for treating one or more estrogen related diseases |
| WO2025155903A1 (en) * | 2024-01-19 | 2025-07-24 | Temple University-Of The Commonwealth System Of Higher Education | Compositions of antioxidant translation modulators for treating neurodegenerative disorders |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3135743A (en) | 1960-06-29 | 1964-06-02 | Sterling Drug Inc | Steroido[2. 3-d]isoxazoles and preparation thereof |
| EP0901489A1 (en) | 1996-05-20 | 1999-03-17 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
| DE19911771B4 (en) * | 1999-03-17 | 2006-03-30 | Zentaris Gmbh | LHRH antagonist, process for its preparation and its use |
| WO2000069859A1 (en) * | 1999-05-14 | 2000-11-23 | Neurocrine Biosciences, Inc. | Imidazo- and pyrrolo[1,2-a]pyrimid-4-ones as gonadotropin-releasing hormone receptor antagonists |
| CA2309395A1 (en) * | 1999-06-04 | 2000-12-04 | Richard Lloyd Bowen | Methods for preventing and treating alzheimer's disease |
| KR20020045609A (en) * | 1999-10-15 | 2002-06-19 | 추후기재 | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| WO2001078780A1 (en) | 2000-04-13 | 2001-10-25 | Takeda Chemical Industries, Ltd. | Preventives/remedies for alzheimer's disease |
| EP1300398B1 (en) | 2000-07-05 | 2006-04-05 | Astellas Pharma Inc. | Propane-1,3-dione derivatives |
-
2002
- 2002-04-27 CN CNB028042964A patent/CN1317030C/en not_active Expired - Fee Related
- 2002-04-27 KR KR10-2003-7014128A patent/KR20040000446A/en not_active Ceased
- 2002-04-27 RU RU2003134949/14A patent/RU2319501C2/en not_active IP Right Cessation
- 2002-04-27 DE DE60227507T patent/DE60227507D1/en not_active Expired - Fee Related
- 2002-04-27 CA CA002444876A patent/CA2444876A1/en not_active Abandoned
- 2002-04-27 UA UA2003109180A patent/UA80679C2/en unknown
- 2002-04-27 ES ES02735312T patent/ES2307760T3/en not_active Expired - Lifetime
- 2002-04-27 HU HU0400067A patent/HUP0400067A2/en unknown
- 2002-04-27 US US10/133,967 patent/US7288517B2/en not_active Expired - Fee Related
- 2002-04-27 AT AT02735312T patent/ATE400287T1/en not_active IP Right Cessation
- 2002-04-27 PL PL36231902A patent/PL362319A1/en not_active Application Discontinuation
- 2002-04-27 MX MXPA03008666A patent/MXPA03008666A/en active IP Right Grant
- 2002-04-27 BR BR0209290-5A patent/BR0209290A/en not_active IP Right Cessation
- 2002-04-27 IL IL15677702A patent/IL156777A0/en unknown
- 2002-04-27 SI SI200230730T patent/SI1392348T1/en unknown
- 2002-04-27 EP EP02735312A patent/EP1392348B1/en not_active Expired - Lifetime
- 2002-04-27 PT PT02735312T patent/PT1392348E/en unknown
- 2002-04-27 SK SK1451-2003A patent/SK14512003A3/en unknown
- 2002-04-27 DK DK02735312T patent/DK1392348T3/en active
- 2002-04-27 JP JP2003504987A patent/JP2004529207A/en not_active Withdrawn
- 2002-04-27 CZ CZ20033167A patent/CZ20033167A3/en unknown
- 2002-04-27 AU AU2002310788A patent/AU2002310788B2/en not_active Ceased
- 2002-04-27 NZ NZ544417A patent/NZ544417A/en unknown
- 2002-04-27 WO PCT/EP2002/004677 patent/WO2002102401A1/en not_active Ceased
-
2003
- 2003-07-10 ZA ZA200305326A patent/ZA200305326B/en unknown
- 2003-09-26 NO NO20034322A patent/NO20034322L/en not_active Application Discontinuation
- 2003-11-10 BG BG108339A patent/BG108339A/en unknown
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