DK167900B1 - Middel til behandling og forebyggelse af haemostatiske forstyrrelser indeholdende vaevsprotein pp4 - Google Patents
Middel til behandling og forebyggelse af haemostatiske forstyrrelser indeholdende vaevsprotein pp4 Download PDFInfo
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- DK167900B1 DK167900B1 DK665787A DK665787A DK167900B1 DK 167900 B1 DK167900 B1 DK 167900B1 DK 665787 A DK665787 A DK 665787A DK 665787 A DK665787 A DK 665787A DK 167900 B1 DK167900 B1 DK 167900B1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
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- A—HUMAN NECESSITIES
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- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C07—ORGANIC CHEMISTRY
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4721—Lipocortins
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Description
DK 167900 B1
Den foreliggende opfindelse angår et middel til behandling og forebyggelse af hæmostatiske forstyrrelser indeholdende vævsprotein PP4.
I DE offentliggørelsesskrift nr. 3.315.000 (US patent-5 skrift nr. 4.507.229) beskrives glycoproteinet PP4, der f.eks. findes i placenta. PP4 har en molekylvægt på 35000 ± 5000 dalton og et isoelektrisk område svarende til en pH--værdi på 4,85 ± 0,15.
Blodkoaguleringshæmmende proteiner kan inddeles i 10 flere grupper på grundlag af deres virkemåde. Både gruppen af proteinaseinhibitorer, f.eks. antithrombin III, og gruppen af proteinaser, f.eks. aktiveret protein C, har til dels uheldige egenskaber til en koaguleringshæmmende behandling, da de enten først virker på de aktiverede koaguleringsen-15 zymers trin eller ved en proteolyse af koaguleringsfaktorer desaktiverer disse, dvs. "forbruger1· dem.
Det er formålet med opfindelsen at tilvejebringe et blodkoaguleringshæmmende middel, der kan forhindre blodkoagulering uden at føre til et forbrug af koaguleringsfak-20 torer.
I DE offentliggørelsesskrift nr. 3.533.516 (side 6--8) beskrives blodkoaguleringshæmmende proteiner, for hvilke der er angivet et isoelektrisk område på 4,4 - 4,6. Disse proteiner isoleres fra intima-laget af større kar, f.eks.
25 aorta eller navlestreng.
I Acta Obst. Gynaec. Jpn. 36, No. 12, 2583-2592 (1984) beskrives ligeledes et koaguleringshæmmende protein fra placenta, der har en molekylvægt på 45000 dalton. I DE offentliggørelsesskrift nr. 3.315.000 (US patentskrift nr.
30 4.507.229) er der også beskrevet følgende egenskaber af PP4:
En elektroforetisk bevægelighed i området mellem bevægeligheden af o^- og a2-globuliner, en sedimentationskoefficient s9 „ på 3,3 ± 0,2 S, en extinktionskoefficient 20,w 35 E2cm (280 P®· 5,9 - °'6' en kulhydratandel på 2,4 ± 0,94% (g/100 g) (mannose 0,3 ± 0,2%, galactose 0,4 ± 0,2%, xylose i-/iv ιυ/^υυ di 2 0,1 ± 0/04%, glukose 0,2 ± 0,1%, glucosamin 1,0 + 2%, neur-aminsyre 0,4 ± 0,2%) og følgende aminosyresammensætning:
Aminosyre Rester pr. 100 rester Variations- 5 (mol-%) koefficient
Lysin 6,95 1,14
Histidin 0,97 17,4
Arginin 5,44 1,77 10 Asparaginsyre 11,41 1,68
Threonin 6,78 2,40
Serin 6,21 2,26
Glutaminsyre 12,25 0,43
Prolin 1,96 6,20 15 Glycin 6,68 3,83
Alanin 7,92 1,67
Cystin 1/2 0,77 19,5
Valin 5,34 3,80
Methionin 1,98 6,00 20 Isoleucin 5,21 2,23
Leucin 11,50 0,45
Tyrosin 3,55 4,21
Phenylalanin 4,07 3,77
Tryptophan 0,93 23,9 25
Det har overraskende vist sig, at dette glycoprotein PP4 udviser blodkoaguleringshæmmende egenskaber.
Opfindelsen angår således et middel til behandling eller forebyggelse af hæmostatiske forstyrrelser, hvilket 30 middel indeholder en virksom mængde PP4 og en farmaceutisk egnet bærer og/eller en stabilisator.
Et sådant middel indeholder i en opløsning fortrinsvis 0,001-100 mg PP4 pr. ml opløsning. Det indgives i en dosis på f.eks. 0,001-50 mg pr. kg legemsvægt en eller flere gange 35 om dagen som bolus eller som langvarig infusion.
Et sådant PP4-holdigt middel fremstilles fortrinsvis enten i fom af et lyophilisat, eventuelt med stabilisatorer DK 167900 B1 3 og tilsætninger som f.eks. albumin, gelatine, salte, sukkerarter og/eller aminosyrer, eller også i form af en blod-isotonisk vandig opløsning, der eventuelt indeholder et baktericid og stabilisatorer som f.eks. albumin, gelatine, 5 salte, sukkerarter og/eller aminosyrer. Opløsningen kan f.eks. indgives ved parenteral injektion eller perfusion.
Også et genteknologisk fremstillet PP4 kan anvendes.
Ved anvendelsen som lasgemiddel bruges PP4 i større mængder.
10 PP4 kan ud fra en vævsekstrakt eller en opløsning bindes til en hydrofob bærermatrix og ved efterfølgende trin- eller gradienteluering befris for urenheder i særdeles vidt omfang.
Før eller efter denne fremgangsmåde kan der eventuelt 15 også gennemføres andre kendte rensningsmetoder, såsom ion-bytningschromatografi, gelfiltrering eller adsorption til calciumphosphat eller hydroxylapatit.
Ved en foretrukket fremgangsmåde til rensning af PP4 bringes den PP4-holdige opløsning ved en pH-værdi på 5,5-20 -9,5, en temperatur på 0-40°C og efter tilsætning af salte, f.eks. efter tilsætning af 50-250 g ammoniumsulfat pr. liter opløsning, magnesiumsulfat eller 0,5-3 mol/liter natrium-chlorid, lithiumchlorid eller kaliumchlorid, i kontakt med et vanduopløseligt hydrofobt adsorptionsmiddel, f.eks. et 25 bærermateriale, der har aliphatiske, aromatiske eller ar-aliphatiske grupper. Som bærermateriale kan der f.eks. anvendes "Sepharose", agarose eller "Fractogel". Som aliphatiske grupper anvendes fortrinsvis alkylgrupper med 1-10 carbonatomer, f.eks. butylgrupper eller octylgrupper, og 30 endvidere f.eks. eventuelt substituerede phenyl- eller phe-nylalanylgrupper eller benzyl- eller substituerede benzyl-grupper. Adsorptionsmidlet skilles derefter fra opløsningen og vaskes eventuelt med en opløsning, der f.eks. indeholder 50-250 g/liter ammoniumsulfat eller 0,5-3 mol/liter natrium-35 chlorid, lithiumchlorid eller kaliumchlorid, og PP4 elueres med en væske med ringere ionstyrke, eventuelt ved hjælp af
LSIY IO/9UU D I
4 en gradient.
Ved en særlig foretrukken udførelsesfonn bringes den PP4-holdige opløsning i kontakt med f.eks. phenyl- eller phenylalanyl-"Sepharose" eller agarose ved en pH-værdi på 5 6-8 efter tilsætning af en opløsning indeholdende 144-243 g ammoniumsulfat pr. liter, men det er ganske særligt foretrukket at bringe den i kontakt med phenyl-MSepharose" ved en pH-værdi på 6,5-7,8 efter tilsætning af en opløsning indeholdende 170-200 g ammoniumsulfat pr. liter. Derefter 10 skilles adsorptionsmidlet fra opløsningen og vaskes f.eks. med en opløsning, der indeholder 176-196 g/liter ammoniumsulfat pr. liter opløsning, og PP4 elueres ved hjælp af en opløsning, der indeholder 114-144 g ammoniumsulfat pr. liter opløsning.
15 Endvidere er det på grund af risikoen for overføring af sygdomme (Hepatitis, AIDS) hensigtsmæssigt ved anvendelse til mennesker at opvarme bestemte biologiske terapeutiske midler, således at infektiøse kim dræbes. Dette betyder dog for det meste aktivitetstab af de biologisk virksomme stof-20 fer.
Det har imidlertid vist sig, at en vandig opløsning af PP4 i nærværelse af calciumioner samt mindst et monoeller oligosaccharid eller sukkeralkohol og eventuelt en aminosyre kan pasteuriseres under vidtgående bibeholdelse 25 af den blodkoaguleringshæmmende evne.
Ved en foretrukken fremgangsmåde til pasteurisering af en PP4-holdig opløsning indstilles opløsningens pH-værdi til 5,0-9,5, og der tilsættes 30-150 g pr. 100 ml opløsning af mindst et mono- eller oligosaccharid eller sukkeralkohol 30 og 0,005-2 mol/liter calciumioner samt eventuelt 0,1-1,5 mol/liter af en aminosyre. Calciumionerne kan f.eks. tilføres i form af calciumsalte, f.eks. som calciumchlorid eller calciumacetat.
Ved en ganske særlig foretrukken udførelsesform sættes 35 der til en PP4-holdig opløsning, der har en pH-værdi på 6,5-8,5, 100-150 g saccharose pr. 100 ml opløsning og 30- DK 167900 B1 5 100 mmol/liter calciumchlorid. Efter opløsning af bestanddelene kan opløsningen f.eks. opvarmes 1-20 timer ved 40--80°C, dog fortrinsvis 8-15 timer ved 55-65°C. Indholdet af PP4 bør ikke være under 20 /zg/ml opløsning. Efter opvarm-5 ningen kan opløsningen f.eks. videreforarbejdes ved koncentrering, dialyse, sterilfiltrering og/eller frysetørring.
Et præparat fremstillet ved den ovenfor beskrevne fremstillings- og pasteuriseringsfremgangsmåde udmærker sig især ved, at PP4 er særdeles vidtgående befriet for uren-10 heder, og at den blodkoaguleringshæmmende virkning er til stede i særdeles vidt omfang.
PP4 kan på gængs måde forarbejdes til et lægemiddel med en fysiologisk acceptabel og farmaceutisk egnet bærer i fast eller flydende form og eventuelt yderligere tilsæt-15 ningsstoffer, såsom stabilisatorer og hjælpestoffer.
Opfindelsen illustreres ved de følgende eksempler.
Eksempel 1
Udvinding af PP4 fra placentavæv og pasteurisering af dette.
20 2 kg dybfrosset placenta homogeniseres i et vævsfindelingsapparat. Homogenisatet vaskes med 3 x l liter fysiologisk natriumchloridopløsning. Placentavævet skilles ved centrifugering fra den ovenstående opløsning. Det vaskede 25 placentahomogenisat suspenderes i 3 liter "Triton X 100"--holdig puffer A (20 mmol/liter tris-HCl, 50 mmol/liter natriumchlorid, 2 g/100 ml "Triton X 100", pH-værdi 7,4), og der omrøres natten over. Ekstrakten fraskilles ved centrifugering, og vævet ekstraheres yderligere med 2 liter 30 puffer A natten over. De to ekstrakter forenes (4,8 liter) og fortyndes med puffer B (20 mmol/liter tris-HCl, 50 mmol/-liter natriumchlorid, pH-værdi 7,5) til 15 liter. Efter tilsætning af 0,75 g DEAE-"Sephadex A 50" pr. liter opløsning omrøres suspensionen i 1 time, adsorbatet skilles fra opløs-35 ningen, vaskes med 40 liter puffer B og derefter med 600 ml puffer B, der indeholder 100 mmol/natriumchlorid, og PP4 DK 167900 B1 6 elueres med puffer B, der indeholder 500 mmol/liter natrium-chlorid. Til eluatet (600 ml) sættes 176 g/liter ammoniumsulfat, og det behandles enten ved en batch-metode eller på en søjle med 300 ml phenyl-,,Sepharose". Den anvendte phenyl-5 "Sepharose" er ækvilibreret i puffer B, som indeholder 3/10 af mætningskoncentrationen af ammoniumsulfat. Efter vaskning med den samme puffer elueres PP4 med puffer B, der indeholder 1/5 af mætningskoncentrationen af ammoniumsulfat. PP4 udfældes ved forøgelse af ammoniumsulfatkoncentrationen til 10 85 g/100 ml eller koncentreres ved ultrafiltrering og vide- reoprenses ved gelfiltrering på "ACA 54". "ACA 54"-søjlen (3 x 100 cm) er ækvilibreret i puffer B, der indeholder 500 mmol/liter natriumchlorid. De PP4-holdige fraktioner forenes.
Efter behov kan der yderligere foretages en pasteu-15 risering som beskrevet i eksempel 3. Opvarmningen kan imidlertid også gennemføres i et andet trin, såsom trinet med DEAE-"Sephadex A 50"-eluatet eller trinet med eluatet fra phenyl-"Sepharose"-behandlingen.
20 Eksempel 2
Bestemmelse af den blodkoaguleringshæmmende aktivitet af PP4
Til bestemmelse af den blodkoaguleringshæmmende aktivitet af det ifølge eksempel 1 fremstillede PP4 anvendes 25 en modificeret prothrombintidsbestemmelse (PT) og en modificeret partiel thromboplastintidsbestemmelse (PTT). a) modificeret PT-bestemmelse.
Til 50 jLtl humant standardplasma sættes 150 μΐ puffer A (20 mmol/liter tris-HCl, 142 mmol natriumchlorid, 30 pH-værdi 7,5), 25 μΐ prøve eller puffer B (20 mmol/- liter tris-HCl, 500 mmol/liter natriumchlorid, pH-værdi 7,5) og 25 μΐ thromboplastinopløsning. Efter 3 minutters inkubering ved 37”C startes koaguleringen ved tilsætning af 250 μΐ af en calciumchloridholdig 35 opløsning C (10 mmol/liter Tris/HCl, 80 mmol/liter natriumchlorid, 20 mmol/liter calciumchlorid, pH- 7 DK 167900 B1 værdi 7,9), og koagulerignstiden bestemmes i et Schnitger-Gross-Koagulometer. Koaguleringstiden af kontrollen med puffer B er 60 sekunder. Koaguleringstidens afhængighed af indholdet af PP4 i 5 opløsningen ved den modificerede PT-bestemmelse: PP4-Koncentrat (μΐ/ml) 0 5 10 15 20
Modific. PT-tid (sek.) 60 68 89 111 132,5 10 b) Modificeret PTT-bestemmeise.
Til 100 μΐ humant standardplasma sættes 25 μΐ prøve og 75 μΐ puffer A, der indeholder 100 mmol/liter natriumchlorid, der inkuberes i 3 minutter ved 37°C, tilsættes 50 μΐ MPathromtinn-reagensopløsning, videre-15 inkuberes i 6 minutter ved 37eC, iblandes derefter 50 μΐ kaolin-suspension, og efter yderligere 2 minutter ved 37°C startes koaguleringen ved tilsætning af 100 μΐ calciumchloridopløsning C.
Prøven er i forvejen dialyseret mod puffer A, der 20 indeholder 500 mmol/liter natriumchlorid. En portion "Pathromtim"-reagensopløsning opløses i 1 ml opløsning med 9 g natriumchlorid pr. liter. Koaguleringstiden bestemmes i et Schnitger-Gross-Koagulometer. Koaguleringstiden af kontrollen med puffer A er 70 sekun-25 der.
Koaguleringstidens afhængighed af indholdet af PP4 i opløsningen ved den modificerede PTT-bestemmelse.
PP4-Koncentrat (μΐ/ml) 0 13 17,7 26 30 Modific. PTT-tid (sek.) 70 84 98 129 * DK 167900 B1 8
Eksempel 3
Pasteurisering af en PP4-holdiq opløsning 500 ml af en PP4-holdig opløsning (100 βg PP4/ml) 5 dialyseres mod 20 mmol Tris-HCl, 150 mmol natriumchlorid, pH-værdi 7,5. Derefter tilsættes der 100 g saccharose pr.
100 ml opløsning. Efter fuldstændig opløsning af saccharosen tilsættes 50 mmol/liter calciumchlorid. Efter opvarmning (10 timer/60eC) kan opløsningen dialyseres mod 20 mmol/liter 10 trinatriumcitrat, 60 mmol/liter natriumchlorid, 10 g/liter glycin, pH-værdi 7,0, sterilfiltreres og frysetørres.
Pasteurisering af PP4 (100 ^g/ml) i opløsning - indflydelse af calciumioner på stabiliteten af PP4.
15 Modificeret PT-tid (sek.) Før opvarmning Opvarmning uden calcium Opvarmning med 50 mmol/1 calcium 68 60 68 20
Claims (5)
1. Middel til behandling eller forebyggelse af hæmo-statiske forstyrrelser, indeholdende en virksom mængde PP4 og en farmaceutisk egnet bærer og/eller en stabilisator.
2. Middel ifølge krav 1, kendetegnet ved, at det foreligger i form af en blodisotonisk vandig opløsning, der eventuelt indeholder et baktericid.
3. Middel ifølge krav 1, 10 kendetegnet ved, at det foreligger i form af et lyophilisat, der eventuelt indeholder tilsætninger og stabilisatorer.
4. Middel ifølge krav 1 i flydende og form og indeholdende 0,001-100 mg PP4 pr. ml.
5. Middel ifølge krav 1 i lyophiliseret form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863643182 DE3643182A1 (de) | 1986-12-18 | 1986-12-18 | Arzneimittel enthaltend das gewebeprotein pp4, verfahren zur herstellung von pp4 und zu seiner pasteurisierung sowie die verwendung von pp4 |
| DE3643182 | 1986-12-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK665787D0 DK665787D0 (da) | 1987-12-17 |
| DK665787A DK665787A (da) | 1988-06-19 |
| DK167900B1 true DK167900B1 (da) | 1994-01-03 |
Family
ID=6316431
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK665787A DK167900B1 (da) | 1986-12-18 | 1987-12-17 | Middel til behandling og forebyggelse af haemostatiske forstyrrelser indeholdende vaevsprotein pp4 |
| DK93359A DK35993D0 (da) | 1986-12-18 | 1993-03-26 | Fremgangsmaade til rensning af vaevsprotein pp4 |
| DK036093A DK36093A (da) | 1986-12-18 | 1993-03-26 | Fremgangsmaade til pasteurisering af vaevsprotein pp4 |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK93359A DK35993D0 (da) | 1986-12-18 | 1993-03-26 | Fremgangsmaade til rensning af vaevsprotein pp4 |
| DK036093A DK36093A (da) | 1986-12-18 | 1993-03-26 | Fremgangsmaade til pasteurisering af vaevsprotein pp4 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5097019A (da) |
| EP (3) | EP0457370B1 (da) |
| JP (1) | JP2532535B2 (da) |
| KR (1) | KR960007922B1 (da) |
| AT (2) | ATE75618T1 (da) |
| AU (1) | AU622102B2 (da) |
| CA (1) | CA1338395C (da) |
| DE (3) | DE3643182A1 (da) |
| DK (3) | DK167900B1 (da) |
| ES (2) | ES2042532T3 (da) |
| FI (1) | FI91218C (da) |
| GR (1) | GR3005247T3 (da) |
| PT (1) | PT86393B (da) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE416151B (sv) * | 1978-10-03 | 1980-12-01 | Ake Gunnar Bolmgren | Byggelement jemte mursten for tillverkning av elementet |
| DE3737239A1 (de) * | 1987-11-03 | 1989-10-12 | Behringwerke Ag | Gentechnische herstellung von anticoagulatorischem protein pp4 |
| NZ232813A (en) * | 1989-03-10 | 1992-08-26 | Snow Brand Milk Products Co Ltd | Human fibroblast glycoprotein, cell differentiation, blood vessel endothelial cell growth factor, cellular immunology inforcing factor of 78 or 74 thousand daltons plus or minus two thousand daltons |
| DE3939346A1 (de) * | 1989-11-29 | 1991-06-06 | Behringwerke Ag | Arzneimitel zur subkutanen oder intramuskulaeren applikation enthaltend polypeptide |
| DE4003773A1 (de) * | 1990-02-08 | 1991-08-14 | Behringwerke Ag | Verfahren zur reinigung von lipocortinen |
| US20030220233A1 (en) | 1994-01-24 | 2003-11-27 | Neorx Corporation | Radiolabeled annexins |
| US5968477A (en) * | 1994-01-24 | 1999-10-19 | Neorx Corporation | Radiolabeled annexin conjugates with hexose and a chelator |
| JP2747979B2 (ja) * | 1994-08-19 | 1998-05-06 | 雪印乳業株式会社 | ヒト由来の糖蛋白質からなる生理活性因子を有効成分とする医薬 |
| DE19734648A1 (de) | 1997-08-11 | 1999-02-18 | Dade Behring Marburg Gmbh | Verwendung von Annexinen als Lupus Antikoagulans Kontrolle oder Standard in Gerinnungstesten |
| US7635676B2 (en) * | 2001-02-21 | 2009-12-22 | Alavita Pharmaccuticals, Inc. | Modified annexin proteins and methods for their use in organ transplantation |
| JP2004528025A (ja) * | 2001-02-21 | 2004-09-16 | サーロメッド・インコーポレーテッド | 修飾されたアネキシン蛋白質及び血栓症を防ぐための方法 |
| US7635680B2 (en) * | 2001-02-21 | 2009-12-22 | Alavita Pharmaceuticals, Inc. | Attenuation of reperfusion injury |
| US7645739B2 (en) * | 2001-02-21 | 2010-01-12 | Alavita Pharmaceuticals, Inc. | Modified annexin compositions and methods of using same |
| US20090291086A1 (en) * | 2001-02-21 | 2009-11-26 | Alavita Pharmaceuticals, Inc. | Compositions and Methods for Treating Cerebral Thrombosis and Global Cerebral Ischemia |
| US6982154B2 (en) * | 2002-02-21 | 2006-01-03 | Surromed, Inc. | Modified annexin proteins and methods for treating vaso-occlusive sickle-cell disease |
| GB2542391A (en) * | 2015-09-17 | 2017-03-22 | Annexin Pharmaceuticals Ab | Process of manufacture |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4461833A (en) * | 1982-06-23 | 1984-07-24 | University Patents, Inc. | Chromatographically purifying proteolytic procoagulant enzyme from animal tissue extract |
| DE3237512A1 (de) * | 1982-10-09 | 1984-04-12 | Behringwerke Ag, 3550 Marburg | Verfahren zur pasteurisierung von antihaemophilem kryopraezipitat (ahk) und danach hergestelltes antihaemophiles kryopraezipitat |
| DE3315000A1 (de) * | 1983-04-26 | 1984-10-31 | Behringwerke Ag, 3550 Marburg | Gewebeprotein pp(pfeil abwaerts)4(pfeil abwaerts), verfahren zu seiner gewinnung sowie seine verwendung |
| CA1265446A (en) * | 1985-09-30 | 1990-02-06 | Masahiro Maki | Anticoagulating substance, process for preparing same and anticoagulant comprising same as an effective component |
| DE3724726A1 (de) * | 1987-07-25 | 1989-02-02 | Behringwerke Ag | Verfahren zur reinigung des plazentaren gewebeproteins pp4 |
| US4896172A (en) * | 1987-11-20 | 1990-01-23 | Canon Kabushiki Kaisha | Liquid injection recording apparatus including recording liquid circulation control |
-
1986
- 1986-12-18 DE DE19863643182 patent/DE3643182A1/de not_active Withdrawn
-
1987
- 1987-12-15 DE DE8787118598T patent/DE3778852D1/de not_active Expired - Lifetime
- 1987-12-15 ES ES87118598T patent/ES2042532T3/es not_active Expired - Lifetime
- 1987-12-15 AT AT87118598T patent/ATE75618T1/de not_active IP Right Cessation
- 1987-12-15 ES ES91112381T patent/ES2072490T3/es not_active Expired - Lifetime
- 1987-12-15 AT AT91112381T patent/ATE121940T1/de not_active IP Right Cessation
- 1987-12-15 EP EP91112381A patent/EP0457370B1/de not_active Expired - Lifetime
- 1987-12-15 EP EP87118598A patent/EP0271885B1/de not_active Expired - Lifetime
- 1987-12-15 DE DE3751281T patent/DE3751281D1/de not_active Expired - Fee Related
- 1987-12-15 EP EP19910112543 patent/EP0457371A1/de not_active Withdrawn
- 1987-12-16 FI FI875518A patent/FI91218C/fi not_active IP Right Cessation
- 1987-12-17 KR KR1019870014371A patent/KR960007922B1/ko not_active Expired - Fee Related
- 1987-12-17 DK DK665787A patent/DK167900B1/da not_active IP Right Cessation
- 1987-12-17 PT PT86393A patent/PT86393B/pt not_active IP Right Cessation
- 1987-12-17 JP JP62317626A patent/JP2532535B2/ja not_active Expired - Lifetime
- 1987-12-17 CA CA000555805A patent/CA1338395C/en not_active Expired - Fee Related
- 1987-12-17 AU AU82646/87A patent/AU622102B2/en not_active Ceased
-
1991
- 1991-02-01 US US07/649,552 patent/US5097019A/en not_active Expired - Fee Related
-
1992
- 1992-07-22 GR GR920401341T patent/GR3005247T3/el unknown
-
1993
- 1993-03-26 DK DK93359A patent/DK35993D0/da unknown
- 1993-03-26 DK DK036093A patent/DK36093A/da not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK35993A (da) | 1993-03-26 |
| US5097019A (en) | 1992-03-17 |
| ATE75618T1 (de) | 1992-05-15 |
| FI91218B (fi) | 1994-02-28 |
| ES2072490T3 (es) | 1995-07-16 |
| EP0271885B1 (de) | 1992-05-06 |
| DK36093D0 (da) | 1993-03-26 |
| PT86393B (pt) | 1990-11-20 |
| PT86393A (en) | 1988-01-01 |
| GR3005247T3 (da) | 1993-05-24 |
| DK665787D0 (da) | 1987-12-17 |
| JPS63165328A (ja) | 1988-07-08 |
| DK35993D0 (da) | 1993-03-26 |
| EP0271885A3 (en) | 1988-09-21 |
| FI91218C (fi) | 1994-06-10 |
| KR880007088A (ko) | 1988-08-26 |
| ATE121940T1 (de) | 1995-05-15 |
| KR960007922B1 (ko) | 1996-06-17 |
| DK36093A (da) | 1993-03-26 |
| EP0457370B1 (de) | 1995-05-03 |
| ES2042532T3 (es) | 1993-12-16 |
| EP0457371A1 (de) | 1991-11-21 |
| CA1338395C (en) | 1996-06-11 |
| AU8264687A (en) | 1988-06-23 |
| DE3751281D1 (de) | 1995-06-08 |
| EP0271885A2 (de) | 1988-06-22 |
| AU622102B2 (en) | 1992-04-02 |
| FI875518L (fi) | 1988-06-19 |
| FI875518A0 (fi) | 1987-12-16 |
| EP0457370A1 (de) | 1991-11-21 |
| JP2532535B2 (ja) | 1996-09-11 |
| DE3778852D1 (de) | 1992-06-11 |
| DK665787A (da) | 1988-06-19 |
| DE3643182A1 (de) | 1988-06-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |