ME01648B - Kombinacija inhibitora hmg-coa reduktaze rosuvastatina sa inhibitorom fosfodiesteraze 4,kao što je roflumilast, roflumilast-n-oksid za liječenje inflamatornih plućnih oboljenja - Google Patents
Kombinacija inhibitora hmg-coa reduktaze rosuvastatina sa inhibitorom fosfodiesteraze 4,kao što je roflumilast, roflumilast-n-oksid za liječenje inflamatornih plućnih oboljenjaInfo
- Publication number
- ME01648B ME01648B MEP-2014-9A MEP914A ME01648B ME 01648 B ME01648 B ME 01648B ME P914 A MEP914 A ME P914A ME 01648 B ME01648 B ME 01648B
- Authority
- ME
- Montenegro
- Prior art keywords
- roflumilast
- hmg
- coa reductase
- pharmaceutically acceptable
- inhibitor
- Prior art date
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Claims (34)
1.Farmaceutska kompozicija koja sadrži farmaceutsku formulaciju koja uključuje količinu PDE4 inhibitora, količinu inhibitora HMG-CoA reduktaze i bar jednu farmaceutsku prihvatljivu pomoćnu supstancu, gde je PDE4 inhibitor odabran iz grupe koja se sastoji od ROFLUMILASTA, farmaceutske prihvatljive soli ROFLUMILASTA, ROFLUMILAST-N-oksida i farmaceutske prihvatljive soli ROFLUMILAST-N-oksida, inhibitor HMG-CoA reduktaze je ROSUVASTATIN ili njegova farmaceutski prihvatljiva so, gde prva količina i druga količina zajedno obuhvataju efikasnu količinu za preventivni ili lekoviti tretman inflamatornog plućnog obolenja.
2.Kombinovani proizvod koji sadrži komponente: (A) količinu PDE4 inhibitora; (B) količinu inhibitora HMG-CoA reduktaze; pri čemu prva i druga količina zajedno obuhvataju efikasnu količinu za preventivno ili lekovito lečenje inflamatornog plućnog obolenja, pri čemu je svaka od komponenti (A) i (B) formulisana u smeši sa bar jednom farmaceutskom prihvatljivom pomoćnom supstancom, i gde je PDE4 inhibitor odabran iz grupe koja se sastoji od ROFLUMILASTA, farmaceutski prihvatljive soli ROFLUMILASTA, ROFLUMILAST-N-oksida i farmaceutske prihvatljive soli ROFLUMILAST-N-oksida, a inhibitor HMG-CoA reduktaze je ROSUVASTATIN ili njegova farmaceutski prihvatljiva so.
3.Oprema koja sadrži komponente: (A) farmaceutsku formulaciju koja obuhvata količinu PDE4 inhibitora, u smeši sa bar jednom farmaceutski prihvatljivom pomoćnom supstancom; (B) farmaceutsku formulaciju koja obuhvata količinu inhibitora HMG-CoA reduktaze, u smeši sa bar jednom farmaceutski prihvatljivom pomoćnom supstancom; gde prva i druga količina zajedno obuhvataju efikasnu količinu za preventivno ili lekovito lečenje inflamatornog plućnog obolenja, i gde je PDE4 inhibitor odabran iz grupe koja se sastoji od ROFLUMILASTA, farmaceutski prihvatljive soli ROFLUMILASTA, ROFLUMILAST-N-oksida i farmaceutske prihvatljive soli ROFLUMILAST-N-oksida, a inhibitor HMG-CoA reduktaze je ROSUVASTATIN ili njegova farmaceutski prihvatljiva so.
4.Farmaceutska kompozicija prema zahtevu 1, gde PDE 4 inhibitor je ROFLUMILAST.
5.Farmaceutska kompozicija prema zahtevu 1, gde PDE4 inhibitor je ROFLUMILAST- N- oksid.
6.Farmaceutska kompozicija prema bilo kom od zahteva 1, 4 ili 5, gde inhibitor HMG-CoA reduktazeje ROSUVASTATIN hemi-kalcijum.
7.Farmaceutska kompozicija prema bilo kom od zahteva 1, 4 ili 5, gde inhibitor HMG-CoA reduktazeje ROSUVASTATIN natrijum.
8.Farmaceutska kompozicija prema bilo kom od zahteva 1, 4 ili 5, gde inhibitor HMG-CoA reduktaze je ROSUVASTATIN.
9. Kombinovani proizvod prema zahtevu 2, gde PDE4 inhibitor je ROFLUMILAST.
10. Kombinovani proizvod prema zahtevu 2, gde PDE4 inhibitor je ROFLUMILAST-N-oksid.
11.Kombinovani proizvod prema bilo kom od zahteva 2, 9 ili 10, gde inhibitor HMG-CoA reduktazeje ROSUVASTATIN hemi-kalcijum.
12.Kombinovani proizvod prema bilo kom od zahteva 2, 9 ili 10, gde inhibitor HMG-CoA reduktazeje ROSUVASTATIN natrijum.
13.Kombinovani proizvod prema bilo kom od zahteva 2, 9 ili 10, gde inhibitor HMG-CoA reduktazeje ROSUVASTATIN.
14.Oprema prema zahtevu 3, gde PDE4 inhibitor je Roflumilast.
15.Oprema prema zahtevu 3, gde PDE4 inhibitor je ROFLUMILAST-N-oksid.
16.Oprema prema bilo kom od zahteva 3, 14 ili 15, gde inhibitor HMG-CoA reduktaze je ROSUVASTATIN hemi-kalcijum.
17.Oprema prema bilo kom od zahteva 3, 14 ili 15, gde inhibitor HMG-CoA reduktaze je ROSUVASTATIN natrijum.
18.Oprema prema bilo kom od zahteva 3, 14 ili 15, gde inhibitor HMG-CoA reduktaze je ROSUVASTATIN.
19.Farmaceutska kompozicija prema bilo kom od zahteva 1, 4, 5, 6, 7 ili 8, gde je inflamatorno plućno obolenje odabrano iz grupe koja se sastoji od astme, COPD, skleroze, alveolitisa, sarkoidoze, idiopatične pulmonarne fibroze i pulmonarne hipertenzije.
20.Farmaceutska kompozicija prema bilo kom od zahteva 1, 4, 5, 6, 7 ili 8, pri čemu je inflamatorno plućno obolenje COPD.
21.Kombinovani proizvod prema bilo kom od zahteva 2, 9, 10, 11, 12 ili 13, gde je inflamatorno plućno obolenje odabrano iz grupe koja se sastoji od astme, COPD, skleroze, alveolitisa, sarkoidoze, idiopatične pulmonarne fibroze i pulmonarne hipertenzije.
22.Kombinovani proizvod prema bilo kom od zahteva 2, 9, 10, 11, 12 ili 13, gde je inflamatorno plućno obolenje COPD.
23.Oprema prema bilo kom od zahteva 3, 14, 15, 16, 17 ili 18, gde je inflamatorno plućno obolenje odabrano iz grupe koja se sastoji od astme, COPD, skleroze, alveolitisa, sarkoidoze, idiopatične pulmonarne fibroze i pulmonarne hipertenzije.
24.Oprema prema bilo kom od zahteva 3, 14, 15, 16, 17 ili 18, gde je inflamatorno plućno obolenje COPD.
25.Primena PDE4 inhibitora i inhibitora HMG-CoA reduktaze za proizvodnju medikamenta, prvenstveno farmaceutske kompozicije prema pronalasku, za preventivnu ili lekovitu terapiju inflamatornog plućnog obolenja, pri čemu je PDE4 inhibitor odabran iz grupe koja se sastoji od ROFLUMILASTA, farmaceutski prihvatljive soli ROFLUMILASTA, ROFLUMILAST-N- oksida i farmaceutske prihvatljive soli ROFLUMILAST-N-oksida, a inhibitor HMG-CoA reduktaze je ROSUVASTATIN ili njegova farmaceutski prihvatljiva so.
26.Primena PDE4 inhibitora i inhibitora HMG-CoA reduktaze za proizvodnju uzastopnog ili odvojenog medikamenta za istovremenu primenu, prvenstveno kombinovanog proizvoda ili opreme prema pronalasku, za preventivnu ili lekovitu terapiju inflamatornog plućnog obolenja, pri čemu je PDE4 inhibitor odabran iz grupe koja se sastoji od ROFLUMILASTA, farmaceutski prihvatljive soli ROFLUMILASTA, ROFLUMILAST-N-oksida i farmaceutske prihvatljive soli ROFLUMILAST-N-oksida, a inhibitor HMG-CoA reduktaze je ROSUVASTATIN ili njegova farmaceutski prihvatljiva so.
27.Primena prema bilo kom od zahteva 25 ili 26, gde PDE4 inhibitor je ROFLUMILAST.
28.Primena prema bilo kom od zahteva 25 ili 26, gde PDE4 inhibitor je ROFLUMILAST-N- oksid.
29.Primena prema bilo kom od zahteva 25, 26, 27 ili 28, gde inhibitor HMG-CoA reduktaze je ROSUVASTATIN hemi-kalcijum.
30.Primena prema bilo kom od zahteva 25, 26, 27 ili 28, gde inhibitor HMG-CoA reduktaze je ROSUVASTATIN natrijum.
31.Primena prema bilo kom od zahteva 25, 26, 27 ili 28, gde inhibitor HMG-CoA reduktaze je ROSUVASTATIN.
32.Primena prema bilo kom od zahteva 25 do 31, gde je inflamatorno plućno obolenje odabrano iz grupe koja se sastoji od astme, COPD, skleroze, alveolitisa, sarkoidoze, idiopatične pulmonarne fibroze i pulmonarne hipertenzije.
33.Primena prema bilo kom od zahteva 25 do 31, gde je inflamatorno plućno obolenje COPD.
34.Postupak za pripremanje farmaceutske kompozicije kao što je definisano u bilo kom od zahteva 1, 4, 5, 6, 7, 8, 19 ili 20, koji obuhvata mešanje PDE4 inhibitora ili njegove farmaceutski prihvatljive soli sa inhibitorom HMG-CoA reduktaze ili njegovom farmaceutski prihvatljivom soli.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06116625 | 2006-07-05 | ||
| PCT/EP2007/056683 WO2008003701A2 (en) | 2006-07-05 | 2007-07-03 | Combination of hmg-coa reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases |
| EP11164516.4A EP2359826B1 (en) | 2006-07-05 | 2007-07-03 | Combination of HMG-COA reductase inhibitor rosuvastatin with a phosphodiesterase 4 inhibitor, such as roflumilast, roflumilast-N-oxide for the treatment of inflammatory pulmonary diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ME01648B true ME01648B (me) | 2014-09-20 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2014-9A ME01648B (me) | 2006-07-05 | 2007-07-03 | Kombinacija inhibitora hmg-coa reduktaze rosuvastatina sa inhibitorom fosfodiesteraze 4,kao što je roflumilast, roflumilast-n-oksid za liječenje inflamatornih plućnih oboljenja |
| MEP-2014-91A ME01901B (me) | 2006-07-05 | 2007-07-03 | Kombinacija inhibitora HMG-CoA reduktaze atorvastatina ili simvastatina sa fosfodiesteraza 4 inhibitorom, kao što je roflumilast za lečenje inflamatornih pulmonarnih oboljenja |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2014-91A ME01901B (me) | 2006-07-05 | 2007-07-03 | Kombinacija inhibitora HMG-CoA reduktaze atorvastatina ili simvastatina sa fosfodiesteraza 4 inhibitorom, kao što je roflumilast za lečenje inflamatornih pulmonarnih oboljenja |
Country Status (26)
| Country | Link |
|---|---|
| US (2) | US20100069392A1 (me) |
| EP (3) | EP2359826B1 (me) |
| JP (3) | JP5349302B2 (me) |
| KR (1) | KR101433394B1 (me) |
| CN (3) | CN101484166B (me) |
| AT (1) | ATE535244T1 (me) |
| AU (1) | AU2007271186C1 (me) |
| BR (1) | BRPI0713768A2 (me) |
| CA (1) | CA2656366A1 (me) |
| CY (2) | CY1114742T1 (me) |
| DK (2) | DK2359826T3 (me) |
| EA (2) | EA021461B1 (me) |
| ES (3) | ES2378281T3 (me) |
| HR (2) | HRP20140073T1 (me) |
| IL (3) | IL195433A (me) |
| ME (2) | ME01648B (me) |
| MX (1) | MX2008016123A (me) |
| NO (1) | NO342590B1 (me) |
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| SI (2) | SI2359826T1 (me) |
| UA (3) | UA98466C2 (me) |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011513203A (ja) * | 2008-03-14 | 2011-04-28 | 大塚製薬株式会社 | Mmp−2及び/又はmmp−9阻害剤 |
| CN102671198A (zh) * | 2011-12-17 | 2012-09-19 | 东莞达信生物技术有限公司 | 一种降压降脂复方药及其制备方法 |
| WO2015185658A2 (en) | 2014-06-05 | 2015-12-10 | Medizinische Universität Wien | Methods of diagnosing chronic obstructive pulmonary disease (copd) using novel molecular biomarkers |
| WO2015185656A1 (en) * | 2014-06-05 | 2015-12-10 | Medizinische Universität Wien | Methods of diagnosing chronic obstructive pulmonary disease (copd) using novel molecular biomarkers |
| JP6755240B2 (ja) * | 2014-06-05 | 2020-09-16 | トランスゲニオン−インターナショナル インスティテュート フォー リジェネレイティヴ トランスレイショナル メディシン ゲーエムベーハー | 新規分子バイオマーカーを使用して慢性閉塞性肺疾患(copd)を診断する方法 |
| US12582809B2 (en) | 2018-01-26 | 2026-03-24 | Bt Bidco, Inc. | Treatment of a disease of the gastrointestinal tract with a PDE4 inhibitor |
| WO2020106757A1 (en) | 2018-11-19 | 2020-05-28 | Progenity, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
| CN121197633A (zh) | 2019-12-13 | 2025-12-26 | 比特比德科有限责任公司 | 用于将治疗剂递送至胃肠道的可摄取装置 |
| WO2021218988A1 (zh) * | 2020-04-30 | 2021-11-04 | 中国科学院上海药物研究所 | Prdx1激动剂及其用途 |
| US20240042147A1 (en) * | 2022-08-03 | 2024-02-08 | Chiesi Farmaceutici S.P.A. | Dry powder inhaler |
Family Cites Families (60)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR69216B (me) | 1979-06-15 | 1982-05-07 | Merck & Co Inc | |
| AU548996B2 (en) | 1980-02-04 | 1986-01-09 | Merck & Co., Inc. | Tetrahydro-2h-pyran-2-one derivatives |
| MX7065E (es) | 1980-06-06 | 1987-04-10 | Sankyo Co | Un procedimiento microbiologico para preparar derivados de ml-236b |
| WO1984002131A1 (fr) | 1982-11-22 | 1984-06-07 | Sandoz Ag | Produits analogues de mevalolactone et leurs derives, leurs procedes de production, compositions pharmaceutiques les contenant ainsi que leur utilisation en tant que produits pharmaceutiques |
| US4681893A (en) | 1986-05-30 | 1987-07-21 | Warner-Lambert Company | Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis |
| EP0307342B1 (de) | 1987-07-10 | 1996-01-03 | Hoechst Aktiengesellschaft | 3-Desmethyl-mevalonsäurederivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate auf Basis dieser Verbindungen, ihre Verwendung sowie Zwischenprodukte |
| CA1336714C (en) | 1987-08-20 | 1995-08-15 | Yoshihiro Fujikawa | Quinoline type mevalonolactone inhibitors of cholesterol biosynthesis |
| US4863957A (en) | 1987-12-21 | 1989-09-05 | Rorer Pharmaceutical Corporation | Novel HMG-CoA reductase inhibitors |
| FR2642065B1 (fr) | 1989-01-24 | 1991-05-24 | Lipha | Derives d'acides benzocycloalcenyl dihydroxy alcanoiques, procede de preparation et medicaments les contenant |
| CA2074933C (en) | 1990-11-30 | 2002-12-03 | Masatoshi Chihiro | Thiazole derivatives as active superoxide radical inhibitors |
| JP2648897B2 (ja) | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | ピリミジン誘導体 |
| HU225869B1 (en) | 1992-04-02 | 2007-11-28 | Smithkline Beecham Corp | Compounds with antiallergic and antiinflammatory activity and pharmaceutical compns. contg. them |
| EP0919544B1 (en) * | 1992-04-02 | 2003-05-14 | Smithkline Beecham Corporation | Compounds useful for treating allergic and inflammatory diseases |
| DE59410119D1 (de) * | 1993-07-02 | 2002-06-20 | Byk Gulden Lomberg Chem Fab | Fluoralkoxy substituierte benzamide und ihre verwendung als zyklisch-nukleotid phosphodiesterase-inhibitoren |
| GB9504460D0 (en) | 1995-03-06 | 1995-04-26 | Bayer Ag | N-(3-Benzofuranyl)urea-derivatives |
| DE69525978T2 (de) | 1995-06-06 | 2002-12-19 | Pfizer | Trizyclische 5,6-dihydro-9h-pyrazolo(3,4-c)-1,2,4-triazolo(4,3-alpha)pyridine |
| DE19636150A1 (de) | 1996-09-06 | 1998-03-12 | Asta Medica Ag | N-substituierte Indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender Wirkung |
| DE59913617D1 (de) | 1998-04-28 | 2006-08-03 | Elbion Ag | Indolderivate und deren Verwendung als Inhibitoren der Phosphodiesterase 4. |
| US20010006656A1 (en) | 1999-02-17 | 2001-07-05 | University Of Washington | Methods and compositions for inhibiting inflammation associated with pulmonary disease |
| DE19944161A1 (de) | 1999-09-15 | 2001-03-22 | Bayer Ag | Neue Kombination zur Behandlung von sexueller Dysfunktion |
| US6410563B1 (en) * | 1999-12-22 | 2002-06-25 | Merck Frosst Canada & Co. | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
| MY134008A (en) | 1999-12-22 | 2007-11-30 | Merck Frosst Canada Inc | Subtituted 8-arylquinoline phospohodiestrase-4 inhibitors |
| EP1275388A4 (en) | 2000-02-10 | 2003-11-26 | Takeda Chemical Industries Ltd | Tnf- alpha inhibitors |
| JP2001294526A (ja) * | 2000-02-10 | 2001-10-23 | Takeda Chem Ind Ltd | TNF−α抑制剤 |
| MY123585A (en) | 2000-03-23 | 2006-05-31 | Merck Canada Inc | Tri-aryl-substituted-ethane pde4 inhibitors. |
| US20050102317A1 (en) * | 2000-07-21 | 2005-05-12 | Ali Kamarei | System and method for event calendaring using a customizable rules subset |
| WO2002024194A2 (en) | 2000-09-19 | 2002-03-28 | Novimmune S.A. | Use of statins (hmg-coa reductase inhibitors) for the preparation of medicament as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent |
| US6740666B2 (en) * | 2000-12-20 | 2004-05-25 | Merck & Co., Inc. | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
| HRP20030636B1 (en) * | 2001-02-15 | 2012-05-31 | Nycomed Gmbh | Phthalayinone-piperidino-derivatives as pde4 inhibitors |
| IL157734A0 (en) * | 2001-03-06 | 2004-03-28 | Cellegy Pharma Inc | Pharmaceutical compositions for the treatment of urogenital disorders |
| JP4193435B2 (ja) * | 2002-07-23 | 2008-12-10 | ブラザー工業株式会社 | インクカートリッジ、および、そのインク充填方法 |
| EP1397359B1 (en) * | 2001-05-24 | 2005-08-31 | Merck Frosst Canada & Co. | 1-biaryl-1,8-napthyridin-4-one phosphodiesterase-4 inhibitors |
| ATE296630T1 (de) * | 2001-06-27 | 2005-06-15 | Merck Frosst Canada Inc | Substituierte 8-arylchinoline als pde4-hemmer |
| US20030114469A1 (en) | 2001-09-27 | 2003-06-19 | Cohen David Saul | Combinations |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| WO2004005258A1 (en) * | 2002-07-02 | 2004-01-15 | Merck Frosst Canada & Co. | Di-aryl-substituted-ethane pyridone pde4 inhibitors |
| AU2003294312A1 (en) * | 2002-11-18 | 2004-07-09 | Celgene Corporation | Methods of usig and compositions comprising (-)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide |
| IS7839A (is) | 2002-11-22 | 2004-05-23 | Merck Frosst Canada Ltd. | 4-oxó-1-(3-setið fenýl-1,4-díhýdró-1,8-naftýridín-3-karboxamíð fosfódíesterasa-4 hindrar |
| BR0316451A (pt) * | 2002-11-27 | 2005-10-11 | Altana Pharma Ag | Combinação sinergìstica compreendendo roflumilast e formoterol |
| US20050119330A1 (en) * | 2003-03-17 | 2005-06-02 | Kao Peter N. | Use of antiproliferative agents in the treatment and prevention of pulmonary proliferative vascular diseases |
| WO2004091626A1 (en) * | 2003-04-07 | 2004-10-28 | Osteoscreen, Inc. | Bone growth stimulation with no/statin and other no modulating combinations |
| WO2004089940A1 (en) | 2003-04-11 | 2004-10-21 | Glenmark Pharmaceuticals S.A. | Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them |
| JP2006524638A (ja) * | 2003-04-30 | 2006-11-02 | メルク フロスト カナダ リミテツド | 8−(3−ビアリール)フェニルキノリン系ホスホジエステラーゼ−4阻害薬 |
| WO2004098578A2 (en) * | 2003-05-12 | 2004-11-18 | Altana Pharma Ag | Composition comprising a pde4 inhibitor and a tnf-alfa antagonist selected from infliximab, adalimumab, cdp870 and cdp517 |
| WO2004103407A2 (en) * | 2003-05-22 | 2004-12-02 | Altana Pharma Ag | Composition comprising a pde4 inhibitor and a pde5 inhibitor |
| WO2005000217A2 (en) * | 2003-06-06 | 2005-01-06 | Merck & Co., Inc. | Combination therapy for the treatment of dyslipidemia |
| US20060160834A1 (en) * | 2003-06-06 | 2006-07-20 | Fong Tung M | Combination therapy for the treatment of hypertension |
| DE10348646A1 (de) | 2003-10-15 | 2005-05-25 | Gkn Driveline International Gmbh | Rollbalg mit großem Krümmungsradius |
| WO2005102348A1 (en) * | 2004-04-19 | 2005-11-03 | Loma Linda University | Composition and method of decreasing renal ischemic damage |
| WO2005102317A1 (en) * | 2004-04-23 | 2005-11-03 | Celgene Corporation | Methods of using and compositions comprising pde4 modulators for the treatment and management of pulmonary hypertension |
| ES2257152B1 (es) * | 2004-05-31 | 2007-07-01 | Laboratorios Almirall S.A. | Combinaciones que comprenden agentes antimuscarinicos y agonistas beta-adrenergicos. |
| GB0415789D0 (en) * | 2004-07-15 | 2004-08-18 | Astrazeneca Ab | Novel combination |
| DE102004046236A1 (de) | 2004-09-22 | 2006-03-30 | Altana Pharma Ag | Arzneimittelzubereitung |
| GB0508924D0 (en) | 2005-04-30 | 2005-06-08 | Astrazeneca Ab | New use |
| GB0510207D0 (en) | 2005-05-19 | 2005-06-22 | Astrazeneca Ab | Novel combination |
| PL1894576T3 (pl) | 2005-06-08 | 2011-10-31 | Kowa Co | Nowy środek do obniżania poziomu triglicerydów |
| US7985756B2 (en) * | 2005-10-21 | 2011-07-26 | Braincells Inc. | Modulation of neurogenesis by PDE inhibition |
| AR057555A1 (es) * | 2005-10-27 | 2007-12-05 | Merck Frosst Canada Ltd | Un inhibidor de fosfodiesterasa-4 4-oxo-1-(3-sustituido fenil-1,4-dihidro-1,8-naftiridin-3-carboxamida y un procedimiento de preparacion del mismo |
| SG166829A1 (en) | 2005-11-08 | 2010-12-29 | Ranbaxy Lab Ltd | Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt |
| US20080103105A1 (en) * | 2006-09-22 | 2008-05-01 | Braincells, Inc. | HMG CoA REDUCTASE MEDIATED MODULATION OF NEUROGENESIS |
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