NL8303211A - Nieuwe farmaceutische preparaten op basis van cisplatinum en werkwijze voor het bereiden daarvan. - Google Patents
Nieuwe farmaceutische preparaten op basis van cisplatinum en werkwijze voor het bereiden daarvan. Download PDFInfo
- Publication number
- NL8303211A NL8303211A NL8303211A NL8303211A NL8303211A NL 8303211 A NL8303211 A NL 8303211A NL 8303211 A NL8303211 A NL 8303211A NL 8303211 A NL8303211 A NL 8303211A NL 8303211 A NL8303211 A NL 8303211A
- Authority
- NL
- Netherlands
- Prior art keywords
- cisplatinum
- sterile
- lyophilized
- product
- stable
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 3
- 239000000243 solution Substances 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000004108 freeze drying Methods 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 11
- 229930195725 Mannitol Natural products 0.000 claims description 11
- 239000000594 mannitol Substances 0.000 claims description 11
- 235000010355 mannitol Nutrition 0.000 claims description 11
- 239000008227 sterile water for injection Substances 0.000 claims description 10
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 239000008223 sterile water Substances 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims 3
- 241000282412 Homo Species 0.000 claims 2
- 238000011275 oncology therapy Methods 0.000 claims 2
- 230000002349 favourable effect Effects 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000008215 water for injection Substances 0.000 description 11
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- 230000008014 freezing Effects 0.000 description 7
- 238000007710 freezing Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000013543 active substance Substances 0.000 description 6
- 229910052697 platinum Inorganic materials 0.000 description 6
- 150000004985 diamines Chemical class 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- -1 cis-platinum (II) diamine Chemical class 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012864 cross contamination Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000013536 elastomeric material Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229920005555 halobutyl Polymers 0.000 description 1
- 125000004968 halobutyl group Chemical group 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910021432 inorganic complex Inorganic materials 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011123 type I (borosilicate glass) Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2339682 | 1982-09-23 | ||
| IT23396/82A IT1153974B (it) | 1982-09-23 | 1982-09-23 | Composizioni farmacologiche a base di cisplatino e metodo per il loro ottenimento |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8303211A true NL8303211A (nl) | 1984-04-16 |
Family
ID=11206716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8303211A NL8303211A (nl) | 1982-09-23 | 1983-09-16 | Nieuwe farmaceutische preparaten op basis van cisplatinum en werkwijze voor het bereiden daarvan. |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4670262A (cs) |
| JP (1) | JPS5978117A (cs) |
| AT (1) | AT382077B (cs) |
| AU (1) | AU559499B2 (cs) |
| BE (1) | BE897761A (cs) |
| CA (1) | CA1211372A (cs) |
| CH (1) | CH655852A5 (cs) |
| DE (1) | DE3333024A1 (cs) |
| DK (1) | DK157168C (cs) |
| FI (1) | FI78236C (cs) |
| FR (1) | FR2533439B1 (cs) |
| GB (1) | GB2127291B (cs) |
| GR (1) | GR79055B (cs) |
| IE (1) | IE56173B1 (cs) |
| IL (1) | IL69752A (cs) |
| IT (1) | IT1153974B (cs) |
| NL (1) | NL8303211A (cs) |
| SE (1) | SE464061B (cs) |
| SU (1) | SU1424722A3 (cs) |
| ZA (1) | ZA836904B (cs) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8303657A (nl) * | 1983-10-24 | 1985-05-17 | Pharmachemie Bv | Voor injectie geschikte, stabiele, waterige, zoutzuur bevattende oplossing van cisplatine, alsmede werkwijze ter bereiding daarvan. |
| DK500185A (da) * | 1984-11-02 | 1986-05-03 | Johnson Matthey Plc | Oploeseliggjort platinforbindelse |
| JPH0665648B2 (ja) * | 1985-09-25 | 1994-08-24 | 塩野義製薬株式会社 | 白金系抗癌物質の安定な凍結真空乾燥製剤 |
| JP2524217B2 (ja) * | 1988-04-18 | 1996-08-14 | マルハ株式会社 | 脳機能改善組成物、学習能力増強剤、記憶力増強剤、痴呆予防剤または痴呆治療剤 |
| FI895340A7 (fi) * | 1988-11-14 | 1990-05-15 | Bristol Myers Squibb Co | Hypertoninen cisplatin-liuos |
| US20030148933A1 (en) * | 1990-10-01 | 2003-08-07 | Pharma Mar S.A. | Derivatives of dehydrodidemnin B |
| JPH06192109A (ja) * | 1992-09-04 | 1994-07-12 | Fuji Kagaku Kogyo Kk | 抗腫瘍効果増強剤 |
| FR2759293B1 (fr) * | 1997-02-11 | 1999-04-30 | Ethypharm Lab Prod Ethiques | Microgranules contenant du cisplatine, procede de fabrication, preparation pharmaceutique et utilisation en polychimiotherapie ou en association avec une radiotherapie |
| GB9803448D0 (en) * | 1998-02-18 | 1998-04-15 | Pharma Mar Sa | Pharmaceutical formulation |
| PT1229922E (pt) * | 1999-11-15 | 2007-09-12 | Pharma Mar Sa | Tratamento de cancros com aplidina. |
| UA76718C2 (uk) * | 2000-06-30 | 2006-09-15 | Фарма Мар, С.А. | Протипухлинні похідні аплідину |
| KR20030038812A (ko) * | 2000-10-12 | 2003-05-16 | 파르마 마르, 에스.에이. | 암 치료 방법 |
| AU2002243646B2 (en) | 2001-01-25 | 2006-06-22 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Formulation of boronic acid compounds |
| RU2178702C1 (ru) * | 2001-02-21 | 2002-01-27 | Общество с ограниченной ответственностью "Нобель" | Антираковое средство |
| JP4272991B2 (ja) * | 2001-09-21 | 2009-06-03 | 大日本住友製薬株式会社 | 凍結乾燥製剤 |
| US20050004012A1 (en) * | 2001-10-19 | 2005-01-06 | Ramon Mangues | Use of aplidine for the treatment of pancreatic cancer |
| RU2335294C2 (ru) * | 2003-03-12 | 2008-10-10 | Дана-Фарбер Кэнсер Инститьют, Инк. | Аплидин для лечения множественной миеломы |
| UA83022C2 (uk) * | 2003-03-12 | 2008-06-10 | Фарма Мар, С.А. | Аплідин для комбінованої терапії лейкозу та лімфоми |
| ATE347367T1 (de) * | 2003-10-13 | 2006-12-15 | Zoser B Salama | Pharmazeutische zusammensetzung umfassend oxoplatin und dessen salze |
| US8436190B2 (en) | 2005-01-14 | 2013-05-07 | Cephalon, Inc. | Bendamustine pharmaceutical compositions |
| AU2007220050B2 (en) * | 2006-02-28 | 2013-08-29 | Pharma Mar, S.A. | Improved antitumoral treatments |
| AU2008313627A1 (en) * | 2007-10-19 | 2009-04-23 | Pharma Mar, S.A. | Improved antitumoral treatments |
| RU2010140888A (ru) * | 2008-03-07 | 2012-04-20 | Фарма Мар, С.А. (Es) | Улучшенные противораковые терапии |
| AR072777A1 (es) | 2008-03-26 | 2010-09-22 | Cephalon Inc | Formas solidas de clorhidrato de bendamustina |
| JP5670335B2 (ja) | 2008-09-25 | 2015-02-18 | セファロン、インク． | ベンダムスチン液体製剤 |
| CN107773538B (zh) * | 2016-08-27 | 2022-09-13 | 鲁南制药集团股份有限公司 | 稳定的甲啶铂无菌冻干粉末及其制备工艺 |
| JOP20190254A1 (ar) | 2017-04-27 | 2019-10-27 | Pharma Mar Sa | مركبات مضادة للأورام |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1432562A (en) * | 1972-04-10 | 1976-04-22 | Rustenburg Platinum Mines Ltd | Platinum co-ordination compounds |
| GB1432563A (en) * | 1972-04-10 | 1976-04-22 | Rustenburg Platinum Mines Ltd | Platinum- co-ordination compounds |
| US4053587A (en) * | 1973-04-13 | 1977-10-11 | Research Corporation | Method of treating viral infections |
| US4255417A (en) * | 1976-08-04 | 1981-03-10 | Johnson Matthey, Inc. | Platinum compounds for the irradication of skin blemishes |
| SE445172B (sv) * | 1978-05-30 | 1986-06-09 | Bristol Myers Co | Stabil, steril vattenlosning av cisplatin i enhetsdoseringsform |
| US4273755A (en) * | 1979-08-16 | 1981-06-16 | Mpd Technology Corporation | Preparation of platinum complexes |
| US4302446A (en) * | 1979-10-02 | 1981-11-24 | Bristol-Myers Company | Pharmaceutical compositions |
| AU541056B2 (en) * | 1980-03-31 | 1984-12-13 | Bristol-Myers Company | Pharmaceuticals formulations |
| US4451447A (en) * | 1980-03-31 | 1984-05-29 | Bristol-Myers Company | Pharmaceutical formulations |
-
1982
- 1982-09-23 IT IT23396/82A patent/IT1153974B/it active
-
1983
- 1983-09-12 GB GB08324380A patent/GB2127291B/en not_active Expired
- 1983-09-13 SE SE8304920A patent/SE464061B/sv not_active IP Right Cessation
- 1983-09-13 DE DE3333024A patent/DE3333024A1/de not_active Withdrawn
- 1983-09-13 AU AU19089/83A patent/AU559499B2/en not_active Ceased
- 1983-09-13 AT AT0326283A patent/AT382077B/de active
- 1983-09-14 JP JP58168513A patent/JPS5978117A/ja active Pending
- 1983-09-15 CH CH5037/83A patent/CH655852A5/de not_active IP Right Cessation
- 1983-09-15 FI FI833300A patent/FI78236C/fi not_active IP Right Cessation
- 1983-09-15 SU SU833643499A patent/SU1424722A3/ru active
- 1983-09-15 GR GR72452A patent/GR79055B/el unknown
- 1983-09-15 BE BE0/211538A patent/BE897761A/fr not_active IP Right Cessation
- 1983-09-16 IE IE2172/83A patent/IE56173B1/en unknown
- 1983-09-16 FR FR8314772A patent/FR2533439B1/fr not_active Expired
- 1983-09-16 DK DK424383A patent/DK157168C/da not_active IP Right Cessation
- 1983-09-16 NL NL8303211A patent/NL8303211A/nl not_active Application Discontinuation
- 1983-09-16 IL IL69752A patent/IL69752A/xx unknown
- 1983-09-16 ZA ZA836904A patent/ZA836904B/xx unknown
- 1983-09-20 CA CA000437117A patent/CA1211372A/en not_active Expired
-
1985
- 1985-05-28 US US06/738,436 patent/US4670262A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| SE8304920L (sv) | 1984-03-24 |
| FI78236C (fi) | 1989-07-10 |
| ZA836904B (en) | 1984-10-31 |
| SE8304920D0 (sv) | 1983-09-13 |
| CH655852A5 (de) | 1986-05-30 |
| AU1908983A (en) | 1984-03-29 |
| SE464061B (sv) | 1991-03-04 |
| IT1153974B (it) | 1987-01-21 |
| IL69752A (en) | 1986-07-31 |
| GB2127291A (en) | 1984-04-11 |
| CA1211372A (en) | 1986-09-16 |
| BE897761A (fr) | 1984-01-02 |
| AT382077B (de) | 1987-01-12 |
| DK424383A (da) | 1984-03-24 |
| IE832172L (en) | 1984-03-23 |
| DK157168C (da) | 1990-04-09 |
| SU1424722A3 (ru) | 1988-09-15 |
| US4670262A (en) | 1987-06-02 |
| GB2127291B (en) | 1986-01-15 |
| IL69752A0 (en) | 1983-12-30 |
| ATA326283A (de) | 1986-06-15 |
| GR79055B (cs) | 1984-10-02 |
| JPS5978117A (ja) | 1984-05-04 |
| FR2533439A1 (fr) | 1984-03-30 |
| FR2533439B1 (fr) | 1986-08-14 |
| GB8324380D0 (en) | 1983-10-12 |
| FI833300A7 (fi) | 1984-03-24 |
| DK424383D0 (da) | 1983-09-16 |
| DE3333024A1 (de) | 1984-03-29 |
| DK157168B (da) | 1989-11-20 |
| IT8223396A0 (it) | 1982-09-23 |
| IE56173B1 (en) | 1991-05-08 |
| FI78236B (fi) | 1989-03-31 |
| AU559499B2 (en) | 1987-03-12 |
| FI833300A0 (fi) | 1983-09-15 |
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