NO326277B1 - Anvendelse av terapeutiske kombinasjoner av et vaskulaert malmiddel og et anti-hypertensivt middel for fremstilling av medikament for behandling av sykdom samt et farmasoytisk preparat omfattende disse - Google Patents
Anvendelse av terapeutiske kombinasjoner av et vaskulaert malmiddel og et anti-hypertensivt middel for fremstilling av medikament for behandling av sykdom samt et farmasoytisk preparat omfattende disse Download PDFInfo
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- NO326277B1 NO326277B1 NO20062050A NO20062050A NO326277B1 NO 326277 B1 NO326277 B1 NO 326277B1 NO 20062050 A NO20062050 A NO 20062050A NO 20062050 A NO20062050 A NO 20062050A NO 326277 B1 NO326277 B1 NO 326277B1
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- agent
- vascular
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- blood pressure
- hypertensive
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Abstract
Oppfinnelsen vedrører anvendelse av en kombinasjon av et antiangiogenetisk middel og et antihypertensivt middel for anvendelse ved fremstilling av et medikament for behandling av en sykdomstilstand forbundet med angiogenese i varmblodige pattedyr, så som et menneske. Oppfinnelsen vedrører også farmasøytiske sammensetninger som omfatter et antiangiogenetisk middel og et antihypertensivt middel, til sett med disse og til en fremgangsmåte for behandling av en sykdomstilstand forbundet med angiogenese som omfatteradministrering av en effektiv mengde av en kombinasjon av et anti-angiogenetisk middel og et anti- hypertensivt middel til et varmblodig dyr, så som et menneske.
Description
Den foreliggende oppfinnelse angår anvendelse av terapeutiske kombinasjoner av et vaskulært målmiddel og et anti-hypertensivt middel for fremstilling av medikament for behandling av sykdom samt et farmasøytisk preparat omfattende disse.
Angiogenese, prosessen for dannelse av nye blodkar, spiller en viktig rolle i en rekke normale prosesser som inkluderer embryoutvikling, sårheling, og flere komponenter av kvinnelig reproduktiv funksjon. Uønskede eller patologisk angiogenese har dog vært assosiert med en rekke sykdomstilstander som omfatter diabetisk retinopati, psoriasis, cancer, reumatoid artritt, ateroma, Kaposi's sarkoma og hemangioma (Fan et al., 1995, Trends Pharmacol. Sei. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31).
Angiogenese stimuleres via promosjon av vekst av endotelceller. Flere polypeptider med in wfro-endotel cellevekstpromoverende aktivitet er blitt indentifisert som omfatter sure eller basiske fibroblastvekstfaktorer (aFGF & bFGF) og vaskulær endotel vekstfaktor (VEG F). Vekstfaktoraktiviteten til VEG F er i motsetning til den til FGFs, relativt spesifikk mot endotelceller, på grunn av den begrensede ekspresjon av dens reseptorer. Nylige bevis indikerer at VEG F er en viktig stimulator for både normal og patologisk angiogenese (Jakeman et al., 1993, Endocrinology, 133: 848-859; Kolch et al., 1995, Breast Cancer Research and Treatment, 36:139-155) og vaksulær permeabilitet (Connolly et al., 1989, J. Biol. Chem. 264: 20017-20024). Endring av vaskulær permeabilitet tenkes også å spille en rolle i både normale og patologiske fysiologiske prosesser (Cullinan-Bove et al., 1993, Endocrinology 133: 829-837; Senger et al., 1993, Cancer and Metastasis Reviews, 112: 303-324).
Derfor forventes antagonisme av aktiviteten til VEGF å være fordelaktig ved en rekke sykdomstilstander, som er forbundet med angiogenese og/eller øket vaskulær permeabilitet, så som cancer, diabetes, psoriasis, reumatoid artritt, Kaposi's sarkoma, hemangioma, akutt og kroniske nefropatier, ateroma, arteriell restenose, autoimmune sykdommer, akutt inflammasjon, overdrevet arrdannelse og adhesjoner, endometriose, dysfunksjonen uterinblødning og okulare sykdommer med retinell karproflierasjon. For eksempel kan antagonisme av VEGF-aktivitet med sekvestrering av VEGF med antistoff resultere i hemming av tumorvekst (Kim et al., 1993, Nature 362: 841-844).
VEGF binder til en reseptor med iboende tyrosinkinaseaktivitet, en såkalt reseptortyrosinkinase (RTK). RTK'er er viktige i transmisjon av biokjemiske signaler over plasmamembranen til celler. Disse transmembrane molekyler består karakteristisk av et ekstracellulært ligandbindende domene som er forbundet gjennom et segment i plasmamembranen til et intracellulært tyrosinkinasedomene. Binding av ligand til reseptoren resulterer i stimulering av reseptorassosiert tyrosinkinaseaktivitet som fører til fosforylering av tyrosinrester på både reseptoren og andre intracellulære molekyler. Disse endringer i tyrosinfosforylering initierer en signalkaskade som fører til en rekke cellulære responser. Inntil nå er det minst blitt definert nitten distinkte RTK-subfamilier, som er definert ved aminosyre-sekvenshomlogi. Én av disse subfamilier omfatter for tiden /ms-lignende tyrosinkinasereseptoren, Fit eller Fitl, den kinaseinsertdomene-holdige reseptoren, KDR (som også kalles FIK-1), og en annen /ims-lignende tyrosin-kinasereseptor, Flt4. To av disse beslektede RTK'er, Fit og KDR, har vært vist å binde VEGF med høy affinitet (De-Vries et al., 1992, Science 255: 989-991; Terman et al., 1992, Biochem. Biophys. Res. Comm. 1992,187:1579-1586). Binding av VEGF til disse reseptorer som er uttrykt I heterologe celler har vært assosiert med endringer i tyrosinfosforyleringstilstanden til cellulære proteiner og kalsiumfluks.
Forbindelser som er inhibitorer av VEGF-reseptortyrosinkinase er beskrevet for eksempel i internasjonale patentsøknader nr. WO 97/22596, WO 97/30035, WO 97/32856, WO 97/34876, WO 97/42187, WO 98/13354, WO 98/13350, WO 99/10349, WO 00/21955 og WO 00/47212.
I normaltilstanden blir mammalt blodtrykk sterkt kontrollert. Det forenkles av en kompleks interaksjon av en rekke formidlere (mediators), hvis effekter holdes på et ekvilibrium. Systemet er slik at hvis nivået til én formidler endrer seg, kompenseres dette for ved de andre formidlerne slik at normalt blodtrykk opprettholdes (for et review av systemer som opprettholder blodtrykket henvises leseren til: Guyton et al., 1972, Annual Review of Physilogy 34,13-46; og Quan et al., 1997, Pacing and Clinical Electrophysiology 20, 764-774). Det er viktig at blodtrykk kontrolleres sterkt fordi hypertensjon, høyt blodtrykk, er grunnlaget for en rekke kardiovaskulære sykdommer, så som slag, akutt myokardiskt infarkt og nyresvikt.
En rekke substanser utviser effekter på blodkarene in vitro noe som isolert sett ville antyde effekter på blodtrykk in vivo. Men på grunn av blodtrykks-kontrollens natur, vil ofte en effekt in vivo bli kompensert for og slik opprettholdes normalt blodtrykk.
Det er blitt rapportert at VEGF og FGF har akutte effekter på vaskulær styrke (tone). VEGF har vært vist å utvide koronærarterier i hund in vitro (Ku et al., 1993, Am J Physiol 265:H585-H592) og å indusere hypotensjon i bevisste rotter (Yang et al., 1996, J Cardiovasc Pharmacol 27:838-844). Disse in vivo-effekter er dog kun forbigående. Selv med svært store doser av VEGF (250 ug/kg) i bevisste rotter, observerte Yang et al. en retur til normalt blodtrykk innen 20 minutter, ved lavere doser returnerte blodtrykket til det normale betraktelig raskere. Boussairi et al. har observert en tilsvarende effekt ved administrasjon av bFGF til bedøvede rotter, med blodtrykk som returnerte til normalt innen 30 minutter etter tilsetning av 15|ig/kg bFGF (J Cardiovasc Pharmacol 1994, 23:99-102). Disse studier viser også at takyfylaksis (eller desensitivisering) utvikler seg raskt etter administrasjon av vekstfaktor. Dvs. at ytterligere administrasjon av vekstfaktor ikke har noen effekt på blodtrykk.
Det er blitt rapportert at vasodilasjon indusert med både FGF og VEGF er avhengig av, i det minste delvis, frisettelse av nitrogenoksyd (NO), noe som også beskrives som endotelavledet relaksfaktor (EDRF), (Morbidelli et al., 1996, Am J Physiol 270:H411-H415 og Wu et al., 1996, Am J Physiol 271 :H1087-H1093).
I internasjonal patentsøknad WO 98/28006 beskrives en fremgangsmåte for å behandle en hypertensiv sykdom i en gravid kvinne, der metoden omfatter administrering til den gravide kvinne av en mengde av en terapeutisk substans som regulerer mengden og/eller aktiviteten til VEGF. I internasjonal patentsøknad WO 00/13703 beskrives en fremgangsmåte for å behandle hypertensjon som omfatter administrering til en pasient en effektiv mengde av en angiogenetisk faktor så som VEGF, eller en agonist av den.
Mens administrasjon av høye nivåer av VEGF til bevisste rotter produserer en forbigående senkning i blodtrykk, som ikke kan anses å være et resultat av takyfylaksis, har vi overraskende funnet at en VEGF-reseptortyrosinkinaseinhibitor fører til en vedvarende økning i blodtrykk i rotter når administrert mer enn en gang, særlig når det blir administrert fortløpende.
Følgelig, i henhold til foreliggende oppfinnelse, frembringes anvendelse av en kombinasjon av et vaskulært målmiddel og et anti-hypertensivt middel valgt fra en kalsiumkanalblokker, en A-ll-antagonist, en ACE-inhibitor eller en B-blokkerfor fremstilling av et medikament for å gi en anti-angiogetisk og/eller vaskulær permeabilitetsreduserende effekt i et varmblodige pattedyr, så som et menneske, hvor det vaskulære målmiddel er valgt blant N-acetylcolchinol-O-fosfat og kombretastatin A4.
I henhold til et annet aspekt ved foreliggende oppfinnelse, frembringes en farmasøytisk sammensetning som omfatter: a) et vaskulært målmiddel eller et farmasøytisk akseptabelt salt, solvat eller prodrug derav, hvor det vaskulære målmiddel er valgt blant N-acetylcolchinol-O-fosfat og kombretastatin A4; b) et anti-hypertensivt middel valgt fra en kalsiumkanalblokker, en A-I I antagonist, en ACE-inhibitor eller en B-blokker eller et farmasøytisk akseptabelt salt, solvat
eller prodrug derav; og eventuelt
c) en farmasøytisk akseptabel bærer eller et fortynningsmiddel.
Kombinasjoner i henhold til oppfinnelsen kan administreres i sekvenser eller
kan administreres samtidig. Når de administreres i sekvenser kan enten det anti-angiogenetiske middel eller det anti-hypertensive middel administreres først.
Et anti-hypertensivt middel er ethvert middel som senker blodtrykk. Det finnes mange forskjellige kategorier av anti-hypertensive midler som omfatter kalsiumkanalblokkere, angiotensinomdannende enzyminhibitorer (ACE-inhibitorer), angiotensin ll-reseptorantagonister (A-ll-antagonister), diuretika, beta-adrenergisk reseptorblokkere (B-blokkere), vasodilatorer og alfa-adrenergisk reseptorblokkere (ot-blokkere). Ethvert anti-hypertensivt middel kan anvendes i henhold til denne oppfinnelse og eksempler fra hver klasse skal gis i det følgende.
Kalsiumkanalblokkere som er innen omfanget av denne oppfinnelse omfatter, men er ikke begrenset til: amlodipin (US patent 4 572 909); bepridil (US patent 3 962 238 eller US gjentrykket 30 577); clentiazem (US patent 4 567 175); diltiazem (US patent 3 562 257); fendilin (US patent 3 262 977); gallopamil (US patent 3 261 859); mibefradil (US patent 4 808 605); prenylamin (US patent 3 152 173); semotiadil (US patent 4 786 635); terodilin (US patent 3 371 014); verapamil (US patent 3 261 859); aranidipin (US patent 4 446 325); barnidipin (US patent 4
220 649); benidipin (europeisk publisert patentsøknad 106 275); cilnidipin (US patent 4 672 068); efonidipin (US patent 4 885 284); elgodipin (US patent 4 952 592); felodipin (US patent 4 264 611); isradipin (US patent 4 466 972); lacidipin (US patent 4 801 599); lercanidipin (US patent 4 705 797); manidipin (US patent 4 892 875); nicardipin (US patent 3 985 758); nifedipin (US patent 3 485 847); nivaldipin (US patent 4 338 322); nimodipin (US patent 3 799 934); nisoldipin (US patent4 154 839); nitrendipin (US patent 3 799 934); cinnarizin (US patent 2 882 271); flunarizin (US patent 3 773 939); lidoflazin (US patent3 267 104); lomerizin (US patent 4 663 325); bencyclan (ungarsk patent 151 865); etafenol (tysk patent 1 265 758); og perhexilin (britisk patent 1 025 578).
Angiotensinomdannende enzyminhibitorer (ACE-inhibitorer) som er innen omfanget til denne oppfinnelse omfatter: alacepril (US patent4 248 883); benazepril (US patent 4 4120 520); captopril (US patent 4 046 889 og 4 105 776); ceronapril (US patent 4 452 790); delapril (US patent 4 385 051); enalapril (US patent 4 374 829); fosinopril (US patent 4 337 201); imidapril (US patent 4 508 727); lisinopril (US patent 4 555 502); moveltipril (belgisk patent 893 553); perindopril (US patent 4 508 729); kinapril (US patent 4 344 949); ramipril (US patent 4 587 258); spirapril (US patent 4 470 972); temocapril (US patent 4 699 905); og trandolapril (US patent 4 933 361). Angiotensin-ll-reseptorantagonister (A-ll-antagonister) som er innenfor omfanget til denne oppfinnelse, omfatter: candesartan (US patent 5 195 444); eprosartan (US patent 5 185 351); irbesartan (US patent 5 270 317); losartan (US patent 5 138 069); og valsartan (US patent 5 399 578).
B-blokkere som er innenfor omfanget til denne oppfinnelse, omfatter: acebutolol (US patent 3 857 952); alprenolol (nederlandsk patentsøknad 6 605 692); amosulalol (US patent 4 217 305); arotinolol (US patent 3 932 400); atenolol (US patent 3 663 607 og 3 836 671); befunolol (US patent 3 853 923); betaxolol (US patent 4 252 984); bevantolol (US patent 3 857 891); bisoprolol (US patent 4 258 062); bopindolol (US patent 4 340 541); bucumolol (US patent 3 663 570); bufetolol (US patent 3 723 476); bufuralol (US patent 3 929 836); bunitrolol (US patent 3 541 130); bupranolol (US patent3 309 406); butidrinhydroklorid (fransk patent 1 390 056); butofilolol (US patent 4 302 601); carazolol (tysk patent 2 240 599); carteolol (US patent 3 910 924); carvedilol (US patent 4 503 067); celiprolol (US patent 4 034 009); cetamolol (US patent 4 059 622); cloranolol (tysk patent 2 213 044); dilevalol (Clifton et al., Journal of Medicinal Chemistry, 1982, 25, 670); epanolol (US patent 4 167 581); indenolol (US patent 4 045 482); labetalol (US patent 4 012 444); levobunolol (US patent 4 463 176); mepindolol (Seeman et al., Heiv. Chim. Acta, 1971, 54, 2411); metipranolol (tsjekkoslovakisk Patentsøknad 128 471); metoprolol (US patent 3 873 600); moprolol (US patent 3 501 769); nadolol (US patent 3 935 267); nadoksolol (US patent 3 819 702); nebivalol (US patent 4 654 362); nipradilol (US patent 4 394 382); oxprenolol (britisk patent 1 077 603); penbutolol (US patent 3 551 493); pindolol (sveitsisk patenter 469 002 og 472 404); practolol (US patent 3 408 387); pronetalol (britisk patent 909 357); propranolol (US patent 3 337 628 og 3 520 919); sotalol (Uloth et al., Journal of Medicinal Chemistry, 1966, 9, 88); sulfinalol (tysk patent 2 728 641); talinolol (US patent 3 935 259 og 4 038 313); tertatolol (US patent3 960 891); tilisolol (US patent 4 129 565); timolol (US patent 3 655 663); toliprolol (US patent 3 432 545); og xibenolol (US patent 4 018 824).
Videre kan de anti-hypertensive midler som kan anvendes i henhold til oppfinnelsen og de farmasøytisk akseptable salter av disse, foreligge som prodrug, hydrater eller solvater. Nevnte hydrater eller solvater er også innen omfanget av foreliggende oppfinnelse.
Foretrukne anti-hypertensive midler ifølge oppfinnelsen omfatter kalsiumkanalblokkere, A-ll-antagonister, ACE-hemmere og B-blokkere.
Mer foretrukket omfatter de anti-hypertensive midler ifølge oppfinnelsen ACE-hemmere, særlig lisinopril og kaptopril.
De anti-hypertensive midler beskrevet heri, er generelt kommersielt tilgjengelige eller de kan fremstilles ved standardteknikker som omfatter de beskrevet i henvisningene gitt tidligere.
Et anti-angiogenetisk middel er ethvert middel som hemmer vekst og opprettholdelse av nye blodkar. Det er mange forskjellige kategorier av anti-angiogenetiske midler som omfatter: midler som hemmer virkningen av vekstfaktorer, anti-invasive midler og vaskulære målmidler.
Midler som hemmer virkningen til vekstfaktorer omfatter:
(i) reseptorantagonister, for eksempel et anti-VEGF-reseptorantistoff (Genentech, kanadisk patentsøknad 2213833); (ii) proteinkinase-C-inhibitorer; (iii) tyrosinkinaseinhibitorer, for eksempel inhibitorer av VEGF-reseptortyrosinkinase, så som SU 5416 (Sugen, publisert internasjonal patentsøknad WO 96/40116); og (iv) modulatorere for signaliseringen til reseptorene Tie-1 og/eller Tie 2; (v) hemmere av proteinekspresjon, for eksempel inhibitorer av VEGF-ekspresjon, så som RPI 4610 (Ribozyme, US patent 4 987 071).
Anti-invasive midler omfatter matriksmetalloproteinaseinhibitorer og urokinaseplasminogenaktivator-reseptorantagonister og urokinaseplasminogen-aktivatorinhibitorer. Matriksmetalloproteinaseinhibitorer omfatter: prinomastat (Agouron, US patent 5 753 653); ilomastat (Glycomed, publisert internasjonal patentsøknad WO 92/9556); marimastat (British Biotechnology, publisert internasjonal patentsøknad WO 94/2447; og batimastat (British Biotechnology, publisert internasjonal patentsøknad WO 90/5719). Urokinaseplasminogen-aktivatorreseptorantagonister omfatter: forbindelser beskrevet i publisert internasjonal patentsøknad WO 96/40747 og forbindelser beskrevet i publisert internasjonal patentsøknad WO 2000001802. Urokinaseplasminogenaktivator-inhibitorer omfatter: forbindelser beskrevet i publisert internasjonal patentsøknad WO 2000005245.
Vaskulære målmidler omfatter: kombretastatin A4 (Bristol Myers Squibb, US patent 4 996 237); og vaskulære destruksjonsmidler beskrevet i publisert internasjonal patentsøknad WO 99/02166 og WO 00/. Et spesielt foretrukket vaskulær destruksjonsmiddel er N-acetylcolchinol-O-fosfat (eksempel 1 fra WO 99/02166).
En rekke former for prodrugs er velkjente i faget. For eksempler på slike prodrugderivater se: a) Design of Prodrugs, redigert av H. Bundgaard, (Elsevier, 1985) og Mewthods in Enzymology, vol. 42, s. 309-396, redigert av K. Widder, et al., (Academic Press, 1985); b) A Textbook of Drug Design and Development, redigert av Krogsgaard-Larsen og H. Bundgaard, kapittel 5, Design and Application of Prodrugs, av H. Bundgaard, s. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8,1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); og
e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
En in wVo-hydrolyserbar ester av en forbindelse med formel I, formel II eller
formel III som inneholder en karboksygruppe, er for eksempel en farmasøytisk akseptabel ester som er hydrolysert i menneske- eller dyrekroppen og frembringer modersyren, for eksempel en farmasøytisk akseptabel ester dannet med en (1-6C)alkohol, så som metanol, etanol, etylenglykol, propanol eller butanol, eller med en fenol eller benzylalkohol, så som fenol eller benzylalkohol eller en substituert fenol eller benzylalkohol der substituenten er for eksempel en halogen (så som fluor eller klor), (1-4C)alkyl (så som metyl) eller (1-4C)alkoksy (så som etoksy) gruppe. Uttrykket omfatter også a-acyloksyalkylestere og beslektede forbindelser med nedbrytning som gir moderhydroksygruppen. Eksempler på a-acyloksyalkylestere omfatter acetoksymetoksykarobnyl og 2,2-dimetylpropionyloksymetoksy-karbonyl.
En in wVo-hydrolyserbar ester av en forbindelse med formel I, formel II eller formel III som inneholder en hydroksygruppe, er for eksempel en farmasøytisk akseptabel ester som hydrolyserer i menneske- eller dyrekroppen til moder-alkoholen. Uttrykket omfatter uorganiske estere, så som fosfatestere og oc-acyloksyalkyletere og beslektede forbindelser som, som et resultat av in vivo-hydrolysen av esteren, brytes ned til moderhydroksygruppen. Eksempler på a-acyloksyalkyletere omfatter acetoksymetoksy og 2,2-dimetylpropionyloksy-metoksy. Et utvalgt av in wVo-hydrolyserbare esterdannende grupper for hydroksy omfatter alkanoyl, benzoyl, fenylacetyl og substituert benzoyl og fenylacetyl, alkoksykarbonyl (som gir alkylkarbonatestere), dialkylkarbamoyl og N-(dialkyl-aminoetyl)-N-alkylkarbamoyl (som gir karbamaer), dialkylaminoacetyl og karboksy-acetyl.
En egnet verdi for et in wVo-hydrolyserbart amid av en forbindelse med formel I som inneholder en karboksygruppe er for eksempel et N-(1-6C)alkyl eller N,N-di-(1-6C)alkylamid, så som N-metyl, N-etyl, N-propyl, N,N-dimetyl, N-etyl-N-metyl eller N,N-dietylamid.
Et egnet farmasøytisk akseptabelt salt av en forbindelse med formel I, formel II eller formel III er for eksempel et syreaddisjonssalt av en forbindelse med formel I, formel II eller formel III som er tilstrekkelig basisk, for eksempel et syreaddisjonssalt med en uorganisk eller organisk syre, så som saltsyre, hydrogenbromidsyre, svovelsyre, trifluoreddiksyre, sitronsyre eller maleinsyre, eller for eksempel et salt av en forbindelse med formel I som er tilstrekkelig sur, for eksempel et alkali eller jordalkalimetallsalt, så som et kalsium eller magnesiumsalt, eller et ammoniumsalt, eller et salt med en organisk base så som metylamin, dimetylamin, trimetylamin, piperidin, morfolin eller tris-(2-hydroksyetyl)amin.
De anti-angiogenetiske midler beskrevet heri, kan fremstilles ved standardteknikker som omfatter de beskrevet i patentsøknadene beskrevet.
Oppfinnelsen skal nå illustreres ved eksempel og med henvisning til den vedlagte figur.
Fig. 1 viser effekten av en VEGF-reseptortyrosinkinaseinhibitor [4-(4-brom-2-fluoranilin)-6-metoksy-7-(1 -metylpiperidin-4-ylmetoksy)kinazolin] på det diastoliske blodtrykk i rotter.
Eksempel 1
Måling av blodtrykk i bevisste rotter ved radiotelemetri
Blodtrykk ble målt ved å anvende data Sciences radio-telemetriutstyr (Data Sciences International, Saint Paul, Minnesota, USA). Dette gir et utstyr for fjernstyrt måling av blodtrykk (BP), puls og aktivitet til en bevisst ubundet rotte. Målingene oppnådd ved å bruke dette systemet er frie for stress som induseres ved kirurgi og tvang. Systemet omfatter en trykkomformer (TA11PA-C40)
(implantatet) som implanteres i buken til en rotte og som formidler et radiosignal som indikerer trykket i aorta til dyret. Signalet mottas av en mottaker (RA1010) som er plassert under plastikkburet som huser dyret. Signal evalueres og nedtegnes automatisk med en forut skrevet datamaskinmykvare (DataQuest IV installert på en IBM-kompatibel PC, som inneholder en Intel™ 486 prosessor).
Implantasjonsmetodologi
Rotter ble bedøvet med "Fluothane™"-inhalasjonsbedøvelse. Buken til rottene ble barbert og huden ble dekket med et topisk disinfeksjonsmiddel. Et snitt ble gjort i den ytre hud for å fristille bukmuskelveggen som ble snittet langs midtlinjen og åpnet. Dyrets indre organer ble holdt tilbake med klammer (retractors), og bukens aorta ble lokalisert. Aortaen ble renset for bindevev over en lengde på 2-3 cm og forsiktig skilt fra den assosierte hulvene. Forsiktighet ble utvist for å sikre at området av aorta som ble preparert var under de renale arterier for å unngå en potensiell okklusjon av nyrene etter kirurgi.
Et bånd ble plassert løst under aorta som deretter ble løftet for å okkludere karet. En punktering ble gjort i karet ved å bruke en 21 standard størrelsesnål (Micro Lance, Becton Dickinson) der spissen tidligere var blitt bøyd til omkring 90 grader i forhold til nålskaftet. Ved å bruke den bøyde kanten til nålen (som ble holdt på plass i karet), ble spissen til implantatkateteret forsiktig ført inn i karet. Etter å ha trukket tilbake nålespissen, ble en liten dråpe kirurgisk lim (Vet Bond 3M) kjørt ned kateteret for å danne forsegling mellom kateteret og blodkaret.
Implantatet ble belagt med et fint nett som ble bruk for å sy implantat-kroppen fast til innsiden av bukveggen. Bukmuskelveggen ble lukket med absorberbare sting. Endene på stingene ble klippet, og den ytre hud til dyret ble lukket ved å bruke kirurgiske autoklips. Disse autoklips ble fjernet 7 dager etter kirurgi.
Generell studieprotokoll
Wistar hannrotter ble implantert (som beskrevet ovenfor). Etter fjerning av kirurgiske autoklips, ble alle rottene håndtert daglig for å akklimatisere dem til doseringsteknikkene. Dyrene ble deretter dosert med bærer (1% polysorbat i vann) i en ytterligere uke.
Blodtrykksdata ble nedtegnet for hvert dyr hvert 10 minutt i løpet av studien. Dyrene ble huset i en omgivelse som hadde en 12 timers syklus med lys og mørke. Normal rotteoppførsel ble observert i løpet av studien, dvs. dyrene hvilte under lysfasen og var aktive under den mørke fase. For å oppnå mer reproduser-bare basale målinger, ble alle de nedtegnende dataene erholdt i løpet av de 12 timene i lysfasen når forsøksdyrene var inaktive. Denne gjennomsnittlige blodtrykksmåling på dagtid for hver rotte ble beregnet i løpet av en 4 dagers periode direkte forut for begynnelse av dosering med forbindelse.
4-(4-brom-2-fluoranilin)-6-metoksy-7-(1-metylpiperidin-4-ylmetoksy)-kinazolin ble dosert p.o. i 12,5 mg/kg en gang daglig i 10 dager. I de neste 4 dagene (dvs. dagene 11 til 14 av dosering med forbindelse), ble rottene dosert
med ACE-inhibitoren kaptopril i 30 mg/kg p.o. en gang daglig i tillegg til kinazolin-forbindelsen. Gjennomsnittlig blodtrykk til hver rotte ble beregnet daglig og forskjell mellom daglig beregnet trykk og starttrykket ble uttrykt.
Fig. 1 viser effekten av VEGF-reseptortyrosinkinaseinhibitoren [4-(4-brom-2-fluoranilin)-6-metoksy-7-(1 -metylpiperidin-4-ylmetoksy)kinazolin] på det diastoliske blodtrykk i rotter. Økning av blodtrykk reverseres tilsetning av en ACE-inhibitor, kaptopril. Det presenteres data for en kontrollrotte og tre forskjellige rotter dosert med VEGF-reseptortyrosinkinaseinhibitoren.
Claims (7)
1. Anvendelse av en kombinasjon av et vaskulært målmiddel og et anti-hypertensivt middel valgt fra en kalsiumkanalblokker, en A-ll-antagonist, en ACE-inhibitor eller en B-blokker for fremstilling av et medikament for å gi en anti-angiogetisk og/eller vaskulær permeabilitetsreduserende effekt i et varmblodige pattedyr, så som et menneske, hvor det vaskulære målmiddel er valgt blant N-acetylcolchinol-O-fosfat og kombretastatin A4.
2. Anvendelse ifølge krav 1 eller 2, hvor det vaskulære målmiddel er N-acetylcolchinol-O-fosfat.
3. Anvendelse ifølge krav 1 eller 2, hvor det vaskulære målmiddel er kombretastatin A4.
4. Anvendelse ifølge hvilket som helst av de foregående krav, hvor det anti-hypertensive middel er en ACE-inhibitor.
5. Anvendelse ifølge krav 4, hvor det anti-hypertensive middel er lisinopril eller kaptopril.
6. Anvendelse ifølge hvilket som helst av de foregående krav, hvor den anti-angiogeniske og/eller den vaskulære permeabilitetsreduserende effekt fremskaffes uten å forårsake hypertensjon.
7. Et farmasøytisk preparat omfattende: a) et vaskulært målmiddel eller et farmasøytisk akseptabelt salt, solvat eller prodrug derav, hvor det vaskulære målmiddel er valgt blant N-acetylcolchinol-O-fosfat og kombretastatin A4; b) et anti-hypertensivt middel valgt fra en kalsiumkanalblokker, en A-M antagonist, en ACE-inhibitor eller en B-blokker eller et farmasøytisk akseptabelt salt, solvat eller prodrug derav; og eventuelt c) en farmasøytisk akseptabel bærer eller et fortynningsmiddel.
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| KR (2) | KR20080034523A (no) |
| CN (1) | CN1431902A (no) |
| AT (1) | ATE355065T1 (no) |
| AU (2) | AU4438601A (no) |
| BR (1) | BR0109729A (no) |
| CA (1) | CA2401854A1 (no) |
| CY (1) | CY1107615T1 (no) |
| CZ (1) | CZ299410B6 (no) |
| DE (1) | DE60126923T2 (no) |
| DK (1) | DK1272186T3 (no) |
| EE (1) | EE200200578A (no) |
| ES (1) | ES2280349T3 (no) |
| GB (1) | GB0008269D0 (no) |
| HU (1) | HUP0300426A2 (no) |
| IL (1) | IL151503A0 (no) |
| IS (2) | IS2455B (no) |
| MX (1) | MXPA02009743A (no) |
| NO (2) | NO323467B1 (no) |
| NZ (2) | NZ520938A (no) |
| PL (1) | PL357605A1 (no) |
| PT (1) | PT1272186E (no) |
| RU (1) | RU2002129353A (no) |
| SI (1) | SI1272186T1 (no) |
| SK (1) | SK14302002A3 (no) |
| WO (1) | WO2001074360A1 (no) |
| ZA (1) | ZA200206959B (no) |
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2000
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2001
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- 2001-04-02 SK SK1430-2002A patent/SK14302002A3/sk unknown
- 2001-04-02 AT AT01917305T patent/ATE355065T1/de active
- 2001-04-02 DK DK01917305T patent/DK1272186T3/da active
- 2001-04-02 CA CA002401854A patent/CA2401854A1/en not_active Abandoned
- 2001-04-02 ES ES01917305T patent/ES2280349T3/es not_active Expired - Lifetime
- 2001-04-02 AU AU4438601A patent/AU4438601A/xx active Pending
- 2001-04-02 EP EP07003863A patent/EP1790340A3/en not_active Withdrawn
- 2001-04-02 EE EEP200200578A patent/EE200200578A/xx unknown
- 2001-04-02 SI SI200130715T patent/SI1272186T1/sl unknown
- 2001-04-02 DE DE60126923T patent/DE60126923T2/de not_active Expired - Lifetime
- 2001-04-02 HU HU0300426A patent/HUP0300426A2/hu unknown
- 2001-04-02 KR KR1020087007835A patent/KR20080034523A/ko not_active Ceased
- 2001-04-02 PT PT01917305T patent/PT1272186E/pt unknown
- 2001-04-02 MX MXPA02009743A patent/MXPA02009743A/es active IP Right Grant
- 2001-04-02 JP JP2001572104A patent/JP2003528917A/ja active Pending
- 2001-04-02 CN CN01807430A patent/CN1431902A/zh active Pending
- 2001-04-02 PL PL01357605A patent/PL357605A1/xx not_active Application Discontinuation
- 2001-04-02 NZ NZ520938A patent/NZ520938A/en unknown
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- 2001-04-02 EP EP06003576A patent/EP1658849A3/en not_active Withdrawn
- 2001-04-02 RU RU2002129353/14A patent/RU2002129353A/ru unknown
- 2001-04-02 WO PCT/GB2001/001522 patent/WO2001074360A1/en not_active Ceased
- 2001-04-02 KR KR1020027013170A patent/KR100849149B1/ko not_active Expired - Fee Related
- 2001-04-02 IL IL15150301A patent/IL151503A0/xx unknown
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2002
- 2002-08-29 ZA ZA200206959A patent/ZA200206959B/en unknown
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