NO331734B1 - Anvendelse av et syklopeptid til fremstilling av et medikament for bekjempelse av tumorer ved stralebehandling. - Google Patents
Anvendelse av et syklopeptid til fremstilling av et medikament for bekjempelse av tumorer ved stralebehandling. Download PDFInfo
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- NO331734B1 NO331734B1 NO20011308A NO20011308A NO331734B1 NO 331734 B1 NO331734 B1 NO 331734B1 NO 20011308 A NO20011308 A NO 20011308A NO 20011308 A NO20011308 A NO 20011308A NO 331734 B1 NO331734 B1 NO 331734B1
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- Prior art keywords
- acid
- acceptable salts
- physiologically acceptable
- nme
- cyclo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
Oppfinnelsen vedrører et farmasøytisk preparat syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter, og minst ett kjemo- terapeutikum og/eller et av dets fysiologisk akseptable salter, og/eller en angiogeneseinhibitor og/eller et av dens fysiologisk akseptable salter.
Description
Oppfinnelsens gjenstand er anvendelse av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter til fremstilling av et medikament for bekjempelse av tumorer ved strålebehandling.
Til grunn for oppfinnelsen lå den oppgave å stille til rådighet bedre behandling for pasienter med tumor.
Denne oppgaven ble løst gjennom oppfinnelsen ifølge foreliggende søknad.
Syklo(Arg-Gly-Asp-D-Phe-NMe-Val) er kjent fra EP 0 770 622 og virker fremfor alt som integrininhibitor, idet det særlig hemmer vekselvirkningen mellom oty-, fø- eller p5-integrinreseptorer og ligander, som f eks bindingen av fibrinogen til avfo-integrinreseptoren. Særlig aktivitet utviser forbindelsen i tilfellet med integrinene avp3, otvP5, a,iibP3 samt av|3i, avp6ogOv|38. Denne virkningen kan påvises f eks etter metoden som er beskrevet av J.W. Smith et al. i J. Biol. Chem. 265,12267-12271 (1990).
Den foreliggende oppfinnelse er å anse som utvelgelsesoppfinnelse i forhold til EP 0 770 622.
IWO 98/14192 er det kjent farmasøytiske preparater som inneholder kombinasjonen av ikke-peptidiske vitronektinreseptorantagonister og kjemoterapeutika. Effekten av antiangiogeneseterapi kombinert med en kjemoterapi er beskrevet av J. Folkman i Nature Medicine 1,27-30 (1995).
WO 97/45447 beskriver fremgangsmåter og sammensetninger for inhibering av otvPs-mediert angiogenese. Fra WO 98/31359 er det kjent sammensetninger med0^3, Ov(35 ellerOv^/otvPsintegrin-antagonister.
Aktiviteten av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) i kombinasjon med et kjemoterapeutikum kan påvises i Lewis-lungekarsinomsystemet. Lewis-lungekarsinom påvirkes bare utilstrekkelig ved hjelp av vanlige kjemoterapeutika (Y. Kakeji og B.A. Teicher, Invest. New Drugs 15: 39-48 (1997)). Fremgangsmåten for forsinkelse av tumorveksten gjennomføres analogt med Kakeji (F. Mitjans et al., J. Cell Sei. 108: 2825-2838 (1995)).
Som kjemoterapeutikum kan det anvendes et kjemoterapeutikum fra en gruppe bestående av
a) alkylerende midler,
b) antibiotika,
c) antimetabolitter,
d) biologika og immunmodulatorer,
e) hormoner og deres antagonister,
f) sennepsgassderivater,
g) alkaloider,
h) inhibitorer for matriksmetalloproteinaser (MMP-inhibitorer),
i) proteinkinaseinhibitorer,
k) andre.
Alkylerende midler er f eks busulfan, karboplatin, karmustin, cisplatin, syklofosfamid, dakarbazin, ifosfamid eller lomustin. Antibiotika er f eks bleomycin, doksorubicin (adriamycin), idarubicin eller plikamycin.
Antimetabolitter er f eks sulfonamider eller folsyreantagonister, f eks også 5-fluoruracil (5-FU), merkaptopurin, metotreksat eller tioguanin, eller 5-FU med kalsiumfolinat (leukovorin).
Biologika og immunmodulatorer er f eks interferon a2A, interleukin 2 eller levamisol.
Hormoner og deres antagonister er f eks flutamid, goserelin, mitotan eller tamoksifen. Sennepsgassderivater er f eks melfalan, karmustin eller sennepsgass. Alkaloider er f eks taksaner som docetaksel eller paklitaksel, videre etoposid, vinblastin eller vinovelbin.
Under andre kjemoterapeutika skal det forstås slike som ikke kan innordnes i de ovenfor nevnte grupper, som f eks altretamin, kladribin, gemcitabin, leukovorin, levamisol, pentostatin eller irinotekan.
Inhibitorer for matriksmetalloproteinasene (MMP-inhibitorer) som er beskrevet f. eks. også av M. Wittaker et al. i Current Opinion in Drug Discovery & Development 1, 157-164 (1998), er de etterfølgende forbindelser, f eks baltimastat (BB-94), marimastat (BB-2516), BB-3644, ilomastat, metastat, AG-3340, BAY-12-9566, AE-941/neovastat, CGS-27023A, RS-113456, RS-130830, Ro-32-3555, Ro-31-9790, CT-1746, CT-1418, D-1927, D-2163.
Proteinkinaseinhibitorer er f eks beskrevet av G. McMahon et al. i Current Opinion in Drug Discovery & Development 1,131-146 (1998) og av L.M. Strawn et al. i Exp. Opin. Invest. Drugs 7, 553-573 (1998). Eksempler på reseptortyrosinkinase-inhibitorer er: CGP 79787, SU-101 (HWA 486, Leflunomid, Arava), SU-5416, SU-5271 (PD-153035), PD-173074, SU-6668, ZD-1839, CP-358774.
Det kan også anvendes såkalte prodroge-derivater for angiogeneseinhibitorene og/eller kjemoterapeutikaene, det vil si forbindelser som er omdannet f eks med alkyl-eller acylgrupper, sukkere eller oligopeptider, og som hurtig spaltes i organismen til de aktive forbindelsene. Til prodroge-derivatene hører f eks også kjemoterapeutikumet kapecitabin, som utgjør prodrogen for 5-FU, slik dette er beskrevet f eks i Inpharma nr. 1142,13-14(1998).
Anvendelse av gemcitabin ved tumorbehandlingen er beskrevet f eks av B.J. Braakhuis et al. i Semin-Oncol. 1995 Aug; 22(4 Suppl. 11): 42-6 eller av R.M. Mohammad et al. i Pancreas 1998 Jan; 16 (1): 19-25.
Ytterligere angiogeneseinhibitorer er beskrevet f eks i tabell 1 i WO 9741844. avp3- og avp5-integrininhibitorer er f eks de i EP 0 770 622 nevnte forbindelser.
Et farmasøytisk preparat kan fremstilles idet man bringer syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter og minst ett kjemoterapeutikum og/eller et av dets fysiologisk akseptable salter og/eller en angiogeneseinhibitor og/eller et av dens fysiologisk akseptable salter sammen med minst ett fast, flytende eller halvflytende bærer- eller hjelpestoff i en egnet doseringsform. De således erholdte preparater kan anvendes som legemidler innen human- eller veterinær-medisinen, særlig ved behandling av tumorer. Som bærerstoffer kommer det på tale med organiske eller uorganiske stoffer som egner seg for den enterale (f eks orale, sublinguale eller rektale), parenterale eller topiske (f eks transdermale) applikasjon, og som ikke reagerer med forbindelsene, f eks vann, planteoljer, benzylalkoholer, polyetylenglykoler, glyserolacetat og andre fettsyreglyserider, gelatin, soyalecitin, karbohydrater som laktose eller stivelse, magnesiumstearat, talkum, cellulose. For oral anvendelse tjener særlig tabletter, drasjeer, kapsler, siruper, safter eller dråper, for rektal anvendelse suppositorier, for parenteral applikasjon oppløsninger, fortrinnsvis olje- eller vannoppløsninger, videre suspensjoner, emulsjoner eller implantater, for topisk anvendelse salver, kremer eller plaster. Den aktive forbindelse kan også lyofiliseres og det erholdte lyofilisat anvendes f eks til fremstilling av injeksjonspreparater. Preparatene kan være sterilisert og/eller inneholde hjelpestoffer som konserverings-, stabiliserings- og/eller fuktemidler, emulgatorer, salter for påvirkning av det osmotiske trykk, bufferstoffer, farge- og/eller aromastoffer. De kan også inneholde ytterligere aktive forbindelser, f eks andre blodtrykksenkende eller diuretisk aktive forbindelser, men også vitaminer og/eller mineralsalter, særlig slike som begunstiger de metabolske prosesser.
Slike preparater kan anvendes ved bekjempelse av patologisk angiogene sykdommer, tromboser, hjerteinfarkt, koronare hjertesykdommer, arteriosklerose, tumorer, osteoporose, betennelser og infeksjoner. Som regel anvendes de til tumorbekjempelse, også til inhibering av tumorveksten eller av tumormetastaser.
Syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) kan anvendes i slike kombinasjons-preparater som anvendes til bekjempelse av sykdommer hvor Ov-integriner, særligOvfø og av(35spiller en rolle, hvorved deres hemming er en del av terapien.
Syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) kan anvendes innen tumorterapien, også i kombinasjon med en annen angiogeneseinhibitor,
a) ved kirurgisk fjerning av en tumor,
b) ved strålingsterapi,
c) ved fotodynamisk terapi,
d) sammen med monoklonale antistoffer mot tumorselektive epitoper,
e) sammen med fusjonsproteiner,
f) sammen med peptidvaksiner og
g) ved genterapi.
Doseringen av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) hhv. dets salter, og også kjemoterapeutikaene og/eller angiogeneseinhibitorene ligger fortrinnsvis mellom ca 0,1 og 100 mg, særlig mellom 0,2 og 20 mg, helt spesielt mellom 0,1 og 10 mg per doseringsenhet. Den daglige dosering ligger fortrinnsvis mellom ca 0,001 og 1, særlig mellom 0,002 og 0,2 mg/kg kroppsvekt.
Under en kjemoterapi kan peptider også gis i en dosering på 1-10 mg/kg 2 ganger per uke. Kjemoterapeutikaene kan f eks også administreres ved en dosering på 1-10 mg/kg en gang per uke i alt i 3-4 uker. De spesielle doser for hver pasient avhenger imidlertid av de forskjelligste faktorer, f eks av aktiviteten av den anvendte spesielle forbindelse, av alderen, kroppsvekten, den generelle helsetilstand, arv, av kost, av administreringstidspunkt og -vei, av utskillingshastighet, legemiddelkombinasjon og alvorligheten av den enkelte sykdom som behandlingen gjelder for. Den orale applikasjon er foretrukket.
Oppfinnelsens gjenstand er således anvendelse av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter til fremstilling av et medikament for bekjempelse av tumorer ved strålebehandling..
Anvendelse av de beskrevne farmasøytisk preparater for bekjempelse av patologisk angiogene sykdommer, tromboser, hjerteinfarkt, koronare hjertesykdommer, arterioskle-rose, tumorer, osteoporose, betennelser og infeksjoner, er også mulig..
Anvendelse av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter etter hverandre eller i fysikalsk kombinasjon med et kjemoterapeutikum og/eller et av dets fysiologisk akseptable salter og/eller en angiogeneseinhibitor og/eller et av dens fysiologisk akseptable salter til fremstilling av et legemiddel for bekjempelse av tumorer, er også mulig.
Anvendelse av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dens fysiologisk akseptable salter etter hverandre og/eller i fysikalsk kombinasjon med et kjemoterapeutikum og/eller et av dets fysiologisk akseptable salter til fremstilling av et legemiddel for bekjempelse av tumorer, er også mulig.
Anvendelse av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter etter hverandre i fysikalsk kombinasjon med et kjemoterapeutikum og/eller et av dets fysiologisk akseptable salter for bekjempelse av tumorer, er også mulig.
Bestanddelene i de farmasøytiske preparatene administreres fortrinnsvis i kombinasjon. De kan imidlertid også administreres hver for seg, samtidig eller etter hverandre.
Det kan også anvendes et sett bestående av atskilte pakninger av
(a) en aktiv mengde av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og (b) en aktiv mengde av et kjemoterapeutikum.
Settet inneholder egnede beholdere, som bokser eller kartonger, individuelle flasker, poser eller ampuller. Settet kan f eks inneholde separate ampuller hvor en aktiv mengde av et syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og kjemoterapeutikumet foreligger oppløst eller i lyofilisert form.
Fra WO 9814192 er det kjent forskjellige biologiske tester som er egnet til å bestemme konsentrasjonen av forbindelsene som fremkaller en farmakologisk effekt.
Syklo-(Arg-Gly-Asp-D-Phe-NMe-Val), kjemoterapeutikumet eller angigeneseinhibitoren kan, når det foreligger en syrefunksjon, overføres med en base til det tilhørende syreaddisjonssalt, f eks ved omsetning av ekvivalente mengder av syren og basen i et inert oppløsningsmiddel som etanol, og påfølgende inndamping. For denne omsetningen kommer det særlig på tale med baser som gir fysiologisk akseptable salter. Således kan en syre omdannes med en base (f eks natrium- eller kaliumhydridoksid eller -karbonat) til det tilsvarende metall-, særlig alkalimetall eller jordalkalimetallsalt til det tilsvarende ammoniumsalt.
På den annen side kan en basisk funksjon overføres til det tilhørende syreaddisjonssalt, f eks ved omsetning av ekvivalente mengder av basen og syren i et inert oppløsningsmiddel som etanol, og med påfølgende inndamping. For denne inndampingen kommer det særlig på tale med syrer som gir fysiologisk akseptable salter. Således kan det anvendes uorganiske syrer, f eks svovelsyre, salpetersyre, hydrogenhalogensyrer som saltsyre eller hydrogenbromsyre, fosforsyrer som ortofosforsyre, sulfaminsyre, videre organiske syrer, særlig alifatiske, alisykliske, aralifatiske, aromatiske eller heterosykliske, én- eller flerbasiske karboksyl-, sulfon-eller svovelsyrer, f eks maursyre, eddiksyre, propionsyre, pivalinsyre, dietyleddiksyre, malonsyre, ravsyre, pimelinsyre, fumarsyre, maleinsyre, melkesyre, vinsyre, eplesyre, sitronsyre, glukonsyre, askorbinsyre, nikotinsyre, isonikotinsyre, metan- eller etansulfonsyre, etandisulfonsyre, 2-hydroksyetansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, naftalen-mono- og/eller disulfonsyrer, laurylsvovelsyre. Salter med fysiologisk ikke akseptable syrer, f eks pikrater, kan anvendes til isolering og/eller rensing av forbindelsene med formel (I).
Et farmasøytisk preparat som inneholder en0^3- og/eller en av(35-integrininhibitor og/eller et av dens fysiologisk akseptable salter og minst én MMP-inhibitor og/eller et av dens fysiologisk akseptable salter, samt et farmasøytisk preparat som inneholder en 0^3- og/eller en av(35-integrininhibitor og/eller et av dens fysiologisk akseptable salter og minst én tyrosinkinaseinhibitor og/eller et av dens fysiologisk akseptable salter, er også mulig.
FortrukneOvfø- og avp5-integrininhibitorer er f eks beskrevet i EP 0 770 622, EP 0 710 657, EP 0 820 988, EP 0 820 991, WO 94/12181, WO 94/08577, EP 0 518 586, WO 95/32710, WO 96/00574, WO 96/00730 eller i DE 198 50 131.
Blant MMP-inhibitorene og tyrosinkinaseinhibitorene er de ovenfor nevnte foretrukne.
Eksempel på tester for kombinasjonsterapi:
Retardasjon av tumorvekst analogt med Kakeji (F. Mitjans et al., J. Cell Sei. 108: 2825-2838(1995)): Lewis-lungekarsinomceller (2 x 10E6) ble injisert i 8-10 uker gamle C57BL-mus. Fra den fjerde dag ble syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) (30 mg/kg) administrert i.p daglig. Tumorveksten ble målt daglig (B.A. Teicher et al., Int. J. Cancer 57: 920-925 (1994)). Dersom tumorene nådde et bestemt volum på ca 100 mm<3>, begynte man på dag 7 etter tumorinokulasjonen forskjellige cytotoksiske kombinasjonsterapier gjennom intraperitoneal injeksjon. Eksempler: 5-fluoruracil (30 mg/kg) eller adriamycin (1,8 mg/kg) ble gitt daglig fra dag 7 til 11. Syklofosfamid (150 mg/kg), karmustin (15 mg/kg) eller gemcitabin (2,5 mg/kg) ble gitt på dag 7, 9 og 11. Cisplatin (10 mg/kg) ble gitt på dag 7. Tumorene ble målt tre ganger i uken inntil et volum på ca 500 mm<3>var nådd. Retardasjonen av tumorvekst ble beregnet som den tid som en enkelt tumor trengte for å nå 500 mm sammenlignet med ubehandlede kontroller.
De etterfølgende eksempler vedrører farmasøytiske preparater:
Eksempel A: Injeksjonsglass
En oppløsning av 100 g syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dens fysiologisk akseptable salter, 100 g av kjemoterapeutikumet og 5 g dinatriumhydrogenfosfat innstilles i 6 1 dobbeltdestillert vann med 2 n saltsyre på pH 6,5, det sterilfiltreres, fylles i injeksjonsglass, lyofiliseres under sterile betingelser og lukkes sterilt. Hvert injeksjonsglass inneholder 5 mg av den aktive forbindelse.
Eksempel B: Suppositorier
Man smelter en blanding av syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter, 20 g av kjemoterapeutikumet sammen med 100 g soyalecitin og 1400 g kakaosmør, heller i former og lar det avkjøles. Hvert suppositorium inneholder 20 mg av den aktive forbindelse.
Eksempel C: Oppløsning
Det lages en oppløsning av 20 g syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter, 1 g av kjemoterapeutikumet, 9,38 g NaH2P042 H20, 28,48 Na2HP0412 H20 og 0,1 g benzalkoniumklorid i 940 ml dobbeltdestillert vann. Det innstilles på pH 6,8 og fylles opp til 1 1 og steriliseres ved bestråling. Denne oppløsningen kan anvendes i form av øyedråper.
Eksempel D: Salve
Man blander 500 mg syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter, 500 mg av kjemoterapeutikumet med 99,5 g vaselin under aseptiske betingelser.
Eksempel E: Tabletter
En blanding av 1 kg syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter, 1 kg av kjemoterapeutikumet, 4 kg laktose, 1,2 kg potetstivelse, 0,2 kg talkum og 0,1 kg magnesiumstearat presses på vanlig måte til
tabletter, slik at hver tablett inneholder 10 mg aktiv forbindelse.
Eksempel F: Drasjeer
Analogt med eksempel E presses tabletter som deretter belegges på vanlig måte med et belegg av sakkarose, potetstivelse, talkum, tragant og farvestoff.
Eksempel G: Kapsler
2 kg syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter, 2 kg av kjemoterapeutikumet fylles på vanlig måte i hardgelatinkapsler, slik at hver kapsel inneholder 20 mg av den aktive forbindelse.
Eksempel H: Ampuller
En oppløsning av 1 kg syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter, 1 kg av kjemoterapeutikumet sterilfiltreres i 601 dobbeltdestillert vann, fylles i ampuller, det lyofiliseres under sterile betingelser og lukkes sterilt. Hver ampulle inneholder 10 mg av den aktive forbindelse.
Eksempel I: Sett
Preparat (sett) for parenteral anvendelse.
Preparatet inneholder 500 mg syklo-(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter og 500 mg gemcitabinhydroklorid, og fremstilles på følgende måte: 500 mg av begge forbindelsene oppløses i 40 ml destillert vann. Oppløsningen filtreres under sterile betingelser og fylles i 10 ml ampuller og lyofiliseres. For intravenøs eller intramuskulær injeksjon tilsettes 10 ml 5 %-ig vandig dekstrose.
Claims (1)
1. Anvendelse av syklo(Arg-Gly-Asp-D-Phe-NMe-Val) og/eller et av dets fysiologisk akseptable salter til fremstilling av et medikament for bekjempelse av tumorer ved strålebehandling.
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| Application Number | Priority Date | Filing Date | Title |
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| DE19842415A DE19842415A1 (de) | 1998-09-16 | 1998-09-16 | Pharmazeutische Zubereitung |
| PCT/EP1999/006654 WO2000015244A2 (de) | 1998-09-16 | 1999-09-09 | Pharmazeutische zubereitung enthaltend ein cyclo-peptide und ein chemotherapeutikum oder einen angiogeneseinhibitor |
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| NO20011308D0 NO20011308D0 (no) | 2001-03-15 |
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| NO331734B1 true NO331734B1 (no) | 2012-03-12 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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1998
- 1998-09-16 DE DE19842415A patent/DE19842415A1/de not_active Withdrawn
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1999
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- 1999-09-09 AT AT99969031T patent/ATE292470T1/de active
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- 1999-09-09 AT AT04006076T patent/ATE432707T1/de active
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- 1999-09-09 CA CA002344151A patent/CA2344151A1/en not_active Abandoned
- 1999-09-09 CZ CZ20010932A patent/CZ302908B6/cs not_active IP Right Cessation
- 1999-09-09 CN CNB998133876A patent/CN1201812C/zh not_active Expired - Fee Related
- 1999-09-09 AU AU59758/99A patent/AU765073B2/en not_active Ceased
- 1999-09-09 ES ES04006076T patent/ES2327331T3/es not_active Expired - Lifetime
- 1999-09-09 CN CNB2004100834955A patent/CN100352494C/zh not_active Expired - Fee Related
- 1999-09-09 PL PL348026A patent/PL201902B1/pl not_active IP Right Cessation
- 1999-09-09 ES ES99969031T patent/ES2241363T3/es not_active Expired - Lifetime
- 1999-09-09 PT PT04006076T patent/PT1466615E/pt unknown
- 1999-09-09 DK DK04006076T patent/DK1466615T3/da active
- 1999-09-09 ID IDW20010746A patent/ID29226A/id unknown
- 1999-09-09 DE DE59911881T patent/DE59911881D1/de not_active Expired - Lifetime
- 1999-09-09 SI SI9930792T patent/SI1113809T1/xx unknown
- 1999-09-09 US US09/787,374 patent/US6683051B1/en not_active Expired - Lifetime
- 1999-09-09 PT PT99969031T patent/PT1113809E/pt unknown
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- 1999-09-09 DK DK99969031T patent/DK1113809T3/da active
- 1999-09-09 BR BR9913737-2A patent/BR9913737A/pt not_active Application Discontinuation
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- 1999-09-09 EP EP04006076A patent/EP1466615B1/de not_active Expired - Lifetime
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