RU94045926A - Фармацевтическая композиция, способ ее получения и способ лечения - Google Patents
Фармацевтическая композиция, способ ее получения и способ леченияInfo
- Publication number
- RU94045926A RU94045926A RU94045926/14A RU94045926A RU94045926A RU 94045926 A RU94045926 A RU 94045926A RU 94045926/14 A RU94045926/14 A RU 94045926/14A RU 94045926 A RU94045926 A RU 94045926A RU 94045926 A RU94045926 A RU 94045926A
- Authority
- RU
- Russia
- Prior art keywords
- composition according
- acid
- secretion
- substance
- gastric juice
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims 4
- 239000008194 pharmaceutical composition Substances 0.000 title claims 3
- 239000000203 mixture Substances 0.000 claims 10
- 150000001875 compounds Chemical class 0.000 claims 7
- 230000000844 anti-bacterial effect Effects 0.000 claims 6
- 210000004051 gastric juice Anatomy 0.000 claims 6
- 230000028327 secretion Effects 0.000 claims 6
- 239000000126 substance Substances 0.000 claims 6
- 208000007882 Gastritis Diseases 0.000 claims 3
- 208000007107 Stomach Ulcer Diseases 0.000 claims 3
- 230000003115 biocidal effect Effects 0.000 claims 3
- 201000005917 gastric ulcer Diseases 0.000 claims 3
- 230000002401 inhibitory effect Effects 0.000 claims 3
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical group N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims 2
- 241000590002 Helicobacter pylori Species 0.000 claims 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims 2
- 229940037467 helicobacter pylori Drugs 0.000 claims 2
- 229940126409 proton pump inhibitor Drugs 0.000 claims 2
- 239000000612 proton pump inhibitor Substances 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 229960002626 clarithromycin Drugs 0.000 claims 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 229960003276 erythromycin Drugs 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 229960000381 omeprazole Drugs 0.000 claims 1
- 235000019371 penicillin G benzathine Nutrition 0.000 claims 1
- 229940056360 penicillin g Drugs 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
Claims (13)
1. Фармацевтическая композиция, включающая вещество, оказывающее ингибирующее действие на секрецию желудочного сока, увеличивая тем самым величину pH, и кислоторазлагаемое антибактериальное соединение.
2. Композиция по п.1, отличающаяся тем, что веществом, ингибирующим секрецию желудочного сока, является ингибитор протонного насоса.
3. Композиция по п.2, отличающаяся тем, что ингибитором протонного насоса является 5-метокси-2- {[(4-метокси-3,5-диметил-2-пиридинил)-метил]-сульфинил}-1Н-бензимидазол или его фармацевтически приемлемая соль.
4. Композиция по п.1, эффективная при гастрите и язве желудка, вызванных микробами.
5. Композиция по п.1, эффективная при гастрите и язве желудка, вызванных Helicobacter pylori.
6. Композиция по п.1, отличающаяся тем, что кислоторазлагаемым антибактериальным соединением является бензилпенициллин.
7. Композиция по п.1, отличающаяся тем, что кислоторазлагаемым антибактериальным соединением является слабоосновной антибиотик.
8. Композиция по п.7, отличающаяся тем, что слабоосновным антибиотиком является слабоосновный эритромицин.
9. Композиция по п.7, отличающаяся тем, что антибиотиком является кларитромицин.
10. Способ лечения гастрита и язвы желудка, вызываемых Helicobacter pylori, включающий назначение пациенту, страдающему этими заболеваниями, для приема эффективного количества вещества, оказывающего ингибирующее действие на секрецию желудочного сока и повышающего тем самым внутрижелудочную величину pH, вместе с кислоторазрушаемым антибактериальным соединением в количестве, достаточном для лечения названной инфекции.
11. Фармацевтическая композиция, включающая в качестве активных ингредиентов терапевтически эффективное количество вещества, оказывающего ингибирующее действие на секрецию желудочного сока и повышающего тем самым внутрижелудочную величину pH, и терапевтически эффективное количество кислоторазлагаемого антибактериального соединения.
12. Композиция по п.1 или 11, отличающаяся тем, что в качестве вещества, оказывающего ингибирующее действие на секрецию желудочного сока, она содержит омепразол в количестве от 1 до 200 мг, а кислоторазлагаемое соединение содержится в количестве 250 мг - 10 г.
13. Способ получения композиции, охарактеризованной в п.1, отличающийся тем, что вещество, оказывающее действие на секрецию желудочного сока, повышающее внутрижелудочную величину pH, вводят в тот же препарат, что и кислоторазлагаемое антибактериальное соединение.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9201297-0 | 1992-04-24 | ||
SE9201297A SE9201297D0 (sv) | 1992-04-24 | 1992-04-24 | Synergistic combination |
SE9300029A SE9300029D0 (sv) | 1993-01-08 | 1993-01-08 | Synergistic combination ii |
SE9300029-7 | 1993-01-08 | ||
PCT/SE1993/000327 WO1993021920A1 (en) | 1992-04-24 | 1993-04-20 | Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic |
Publications (2)
Publication Number | Publication Date |
---|---|
RU94045926A true RU94045926A (ru) | 1997-11-27 |
RU2143899C1 RU2143899C1 (ru) | 2000-01-10 |
Family
ID=26661401
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
RU94045926A RU2143899C1 (ru) | 1992-04-24 | 1993-04-20 | Фармацевтическая композиция, способ ее получения и способ лечения |
Country Status (39)
Country | Link |
---|---|
US (3) | US5599794A (ru) |
EP (2) | EP0637241B1 (ru) |
JP (1) | JPH07505901A (ru) |
KR (1) | KR100340165B1 (ru) |
CN (1) | CN1041798C (ru) |
AP (1) | AP466A (ru) |
AT (1) | ATE194286T1 (ru) |
AU (1) | AU669903B2 (ru) |
CA (1) | CA2133762C (ru) |
CZ (1) | CZ291201B6 (ru) |
DE (2) | DE69328967T2 (ru) |
DK (1) | DK0637241T3 (ru) |
DZ (1) | DZ1683A1 (ru) |
EE (1) | EE03149B1 (ru) |
ES (1) | ES2100135T3 (ru) |
FI (1) | FI944953L (ru) |
GR (2) | GR970300011T1 (ru) |
HK (1) | HK1008296A1 (ru) |
HR (1) | HRP930755B1 (ru) |
HU (1) | HUT71225A (ru) |
IL (1) | IL105155A (ru) |
IS (1) | IS3990A (ru) |
LV (1) | LV12625B (ru) |
MA (1) | MA22878A1 (ru) |
MY (1) | MY121189A (ru) |
NO (1) | NO314288B1 (ru) |
NZ (1) | NZ252759A (ru) |
PL (1) | PL173485B1 (ru) |
PT (1) | PT637241E (ru) |
RO (1) | RO115780B1 (ru) |
RU (1) | RU2143899C1 (ru) |
SG (1) | SG52485A1 (ru) |
SI (1) | SI9300219B (ru) |
SK (1) | SK282420B6 (ru) |
TN (1) | TNSN93040A1 (ru) |
TW (1) | TW276996B (ru) |
UA (1) | UA43830C2 (ru) |
WO (1) | WO1993021920A1 (ru) |
YU (1) | YU49091B (ru) |
Families Citing this family (58)
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TW420610B (en) * | 1994-04-07 | 2001-02-01 | Pfizer | A pharmaceutical composition for treating a H. pylori infection or gastric or duodenal ulcers |
SE9500422D0 (sv) * | 1995-02-06 | 1995-02-06 | Astra Ab | New oral pharmaceutical dosage forms |
US6132768A (en) * | 1995-07-05 | 2000-10-17 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors |
US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
US6699885B2 (en) * | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
US6489346B1 (en) * | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
CN1061232C (zh) * | 1996-04-12 | 2001-01-31 | 马理国 | 一种治疗胃炎、溃疡的药物组合物 |
SI9700186B (sl) | 1997-07-14 | 2006-10-31 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. | Nova farmacevtska oblika z nadzorovanim sproscanjem zdravilnih ucinkovin |
AU9067198A (en) * | 1997-07-25 | 1999-02-16 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Proton pump inhibitor in therapeutic combination with antibacterial substances |
US6096340A (en) * | 1997-11-14 | 2000-08-01 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
US6117868A (en) * | 1998-09-16 | 2000-09-12 | Ed. Geistlich Sohne Ag Fur Chemische Industrie | Treatment of gastrointestinal ulcers or gastritis caused by microbial infection |
JP2002537336A (ja) * | 1999-02-26 | 2002-11-05 | ニトロメド インコーポレーテッド | ニトロソ化およびニトロシル化されたプロトンポンプ阻害剤、組成物および使用方法 |
US6852739B1 (en) * | 1999-02-26 | 2005-02-08 | Nitromed Inc. | Methods using proton pump inhibitors and nitric oxide donors |
US6245913B1 (en) | 1999-06-30 | 2001-06-12 | Wockhardt Europe Limited | Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole |
US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
US6316020B1 (en) * | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
US7365047B1 (en) * | 1999-09-28 | 2008-04-29 | The Regents Of The University Of California | Use of pentagastrin to inhibit gastric acid secretion or as a diuretic |
US20020004502A1 (en) | 2000-01-05 | 2002-01-10 | Redmond H. Paul | Treatment of inflammatory bowel disease |
US6787342B2 (en) | 2000-02-16 | 2004-09-07 | Merial Limited | Paste formulations |
AU2001225787C1 (en) * | 2000-02-29 | 2006-09-21 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
EP1263445A1 (en) * | 2000-03-09 | 2002-12-11 | Ian Whitcroft | Treatment of inflammatory dermatoses comprising erythromycin or clarythromycin, metronidazole and a gastrointestinal hydrogen pump inhibitor |
EP1133987A1 (en) * | 2000-03-09 | 2001-09-19 | Ian Whitcroft | Treatment of inflammatory dermatoses with combinations of erythromycin or clarythromycin, metronidazole and a hydrogen pump inhibitor |
BR0109544A (pt) * | 2000-03-28 | 2003-06-10 | Biochemie Gmbh | Partìculas granuladas com sabor ocultado |
SE0002476D0 (sv) | 2000-06-30 | 2000-06-30 | Astrazeneca Ab | New compounds |
US6544556B1 (en) | 2000-09-11 | 2003-04-08 | Andrx Corporation | Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and a proton pump inhibitor |
US20020064555A1 (en) * | 2000-09-29 | 2002-05-30 | Dan Cullen | Proton pump inhibitor formulation |
SE0103695D0 (sv) | 2001-11-07 | 2001-11-07 | Thomas Boren | A novel non-antibiotic strategy against OGIP infections based on a cereal product |
WO2003063927A2 (en) * | 2001-11-16 | 2003-08-07 | Eisai Co. Ltd | Compositions and methods to treat gastrointestinal disorders |
US20040006111A1 (en) * | 2002-01-25 | 2004-01-08 | Kenneth Widder | Transmucosal delivery of proton pump inhibitors |
US20030228363A1 (en) * | 2002-06-07 | 2003-12-11 | Patel Mahendra R. | Stabilized pharmaceutical compositons containing benzimidazole compounds |
AU2003254282A1 (en) * | 2002-08-01 | 2004-02-23 | Nitromed, Inc. | Nitrosated proton pump inhibitors, compositions and methods of use |
JP2006516574A (ja) * | 2003-02-05 | 2006-07-06 | テバ ファーマシューティカル インダストリーズ リミティド | ランソプラゾール安定化方法 |
WO2004073654A2 (en) * | 2003-02-20 | 2004-09-02 | Santarus, Inc. | A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained supression of gastric acid |
US20040185092A1 (en) * | 2003-03-18 | 2004-09-23 | Yih Ming Hsiao | Pharmaceutical preparations of omeprazole and/or clarithromycin for oral use |
JP2006528181A (ja) * | 2003-07-18 | 2006-12-14 | サンタラス インコーポレイティッド | 酸分泌を阻害するために有用な薬学的製剤ならびにそれらを作製および使用する方法 |
US8993599B2 (en) * | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
AU2004257864A1 (en) * | 2003-07-18 | 2005-01-27 | Santarus, Inc. | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders |
US8815916B2 (en) * | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
US8906940B2 (en) * | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
US20060194748A1 (en) * | 2005-02-28 | 2006-08-31 | National University Corporation Nagoya University | Methods for treating disorders induced by H. pylori infections and pharmaceutical compositions for the same |
WO2007070164A1 (en) * | 2005-10-19 | 2007-06-21 | The Curators Of The University Of Missouri | Pharmaceutical composition comprising a proton pump inhibitor, a buffering agent and an anti-h. pylori active substance and methods of using same |
US20070141151A1 (en) * | 2005-12-20 | 2007-06-21 | Silver David I | Lansoprazole orally disintegrating tablets |
GB2459393B (en) | 2006-10-05 | 2010-09-08 | Santarus Inc | Novel capsule formulation for the proton pump inhibitor omeprazole |
US20090092658A1 (en) * | 2007-10-05 | 2009-04-09 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
WO2008057802A2 (en) | 2006-10-27 | 2008-05-15 | The Curators Of The University Of Missouri | Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same |
US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
US10869690B2 (en) * | 2017-06-29 | 2020-12-22 | Ethicon Llc | Trocar obturator with transverse needle ports |
WO2024075017A1 (en) | 2022-10-04 | 2024-04-11 | Zabirnyk Arsenii | Inhibition of aortic valve calcification |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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IL85472A (en) * | 1987-03-09 | 1991-06-30 | Procter & Gamble | Pharmaceutical compositions for treating gastrointestinal disorders |
JP2694361B2 (ja) * | 1989-02-09 | 1997-12-24 | アストラ アクチエボラグ | 抗菌剤 |
EP0382489B1 (en) * | 1989-02-10 | 1994-11-17 | Takeda Chemical Industries, Ltd. | Use of benzimidazole derivatives as antibacterial agents |
GB9018603D0 (en) * | 1990-08-24 | 1990-10-10 | Smith Kline French Lab | Compositions |
AU8445791A (en) * | 1990-09-14 | 1992-04-15 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria |
-
1993
- 1993-03-24 TW TW082102192A patent/TW276996B/zh active
- 1993-03-24 IL IL10515593A patent/IL105155A/en active IP Right Review Request
- 1993-03-24 IS IS3990A patent/IS3990A/is unknown
- 1993-04-02 HR HR930755A patent/HRP930755B1/xx not_active IP Right Cessation
- 1993-04-07 DZ DZ930044A patent/DZ1683A1/fr active
- 1993-04-15 AP APAP/P/1993/000518A patent/AP466A/en active
- 1993-04-20 EP EP93912028A patent/EP0637241B1/en not_active Revoked
- 1993-04-20 JP JP5519164A patent/JPH07505901A/ja active Pending
- 1993-04-20 WO PCT/SE1993/000327 patent/WO1993021920A1/en not_active Application Discontinuation
- 1993-04-20 EP EP99108949A patent/EP0956857A3/en not_active Withdrawn
- 1993-04-20 SG SG1996005136A patent/SG52485A1/en unknown
- 1993-04-20 PT PT93912028T patent/PT637241E/pt unknown
- 1993-04-20 ES ES93912028T patent/ES2100135T3/es not_active Expired - Lifetime
- 1993-04-20 DE DE69328967T patent/DE69328967T2/de not_active Revoked
- 1993-04-20 CA CA002133762A patent/CA2133762C/en not_active Expired - Lifetime
- 1993-04-20 SK SK1275-94A patent/SK282420B6/sk not_active IP Right Cessation
- 1993-04-20 CZ CZ19942593A patent/CZ291201B6/cs not_active IP Right Cessation
- 1993-04-20 PL PL93305799A patent/PL173485B1/pl unknown
- 1993-04-20 UA UA94105962A patent/UA43830C2/uk unknown
- 1993-04-20 RO RO94-01707A patent/RO115780B1/ro unknown
- 1993-04-20 RU RU94045926A patent/RU2143899C1/ru not_active IP Right Cessation
- 1993-04-20 NZ NZ252759A patent/NZ252759A/en not_active IP Right Cessation
- 1993-04-20 HU HU9403069A patent/HUT71225A/hu not_active Application Discontinuation
- 1993-04-20 AT AT93912028T patent/ATE194286T1/de not_active IP Right Cessation
- 1993-04-20 AU AU42737/93A patent/AU669903B2/en not_active Ceased
- 1993-04-20 DK DK93912028T patent/DK0637241T3/da active
- 1993-04-20 DE DE0637241T patent/DE637241T1/de active Pending
- 1993-04-21 MA MA23171A patent/MA22878A1/fr unknown
- 1993-04-21 YU YU27593A patent/YU49091B/sh unknown
- 1993-04-22 US US08/051,722 patent/US5599794A/en not_active Expired - Fee Related
- 1993-04-23 SI SI9300219A patent/SI9300219B/sl not_active IP Right Cessation
- 1993-04-23 TN TNTNSN93040A patent/TNSN93040A1/fr unknown
- 1993-04-23 MY MYPI93000749A patent/MY121189A/en unknown
- 1993-04-24 CN CN93105000A patent/CN1041798C/zh not_active Expired - Fee Related
-
1994
- 1994-10-21 NO NO19944010A patent/NO314288B1/no unknown
- 1994-10-21 FI FI944953A patent/FI944953L/fi not_active Application Discontinuation
- 1994-10-22 KR KR1019940703767A patent/KR100340165B1/ko not_active IP Right Cessation
- 1994-11-17 EE EE9400418A patent/EE03149B1/xx not_active IP Right Cessation
-
1995
- 1995-05-16 US US08/441,766 patent/US5629305A/en not_active Expired - Lifetime
- 1995-05-16 US US08/442,382 patent/US5633244A/en not_active Expired - Lifetime
-
1997
- 1997-05-30 GR GR970300011T patent/GR970300011T1/el unknown
-
1998
- 1998-07-17 HK HK98109224A patent/HK1008296A1/xx not_active IP Right Cessation
-
2000
- 2000-09-21 GR GR20000402159T patent/GR3034470T3/el not_active IP Right Cessation
- 2000-10-16 LV LVP-00-139A patent/LV12625B/en unknown
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