NO335730B1 - Polypeptid og farmasøytisk sammensetning, samt anvendelse derav. - Google Patents
Polypeptid og farmasøytisk sammensetning, samt anvendelse derav. Download PDFInfo
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- NO335730B1 NO335730B1 NO20064121A NO20064121A NO335730B1 NO 335730 B1 NO335730 B1 NO 335730B1 NO 20064121 A NO20064121 A NO 20064121A NO 20064121 A NO20064121 A NO 20064121A NO 335730 B1 NO335730 B1 NO 335730B1
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- Prior art keywords
- peptides
- peptide
- constipation
- seq
- gastrointestinal
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Abstract
Foreliggende oppfinnelse angår sammensetninger og relaterte fremgangsmåter for behandling av IBS og andre gastrointestinale forstyrrelser og tilstander (for eksempel gastrointestinale motilitetsforstyrrelser, funksjonelle gastrointestinale forstyrrelser, gastroøsofagal reflukssykdom (GERD), duodenogastrisk refluks, Crohns sykdom, colitis ulcerosa, inflammatorisk tarmsykdom, funksjonell kardialgi, dyspepsi (omfattende funksjonell dyspepsi eller non-ulcer dyspepsi), gastroparese, kronisk intestinal pseudoobstruksjon (eller colonisk pseudoobstruksjon) og forstyrrelser og tilstander forbundet med konstipasjon, for eksempel konstipasjon forbundet med anvendelse av opiumsholdige smertestillende midler, postkirurgisk konstipasjon (post-operativ ileus), og konstipasjon forbundet med neuropatiske forstyrrelser så vel som andre tilstander og forstyrrelser ved anvendelse av peptider og andre midler som aktiverer guanylat syklase (GC-C)-reseptoren.
Description
TEKNISK OMRÅDE
Foreliggende oppfinnelse angår polypeptid og farmasøytisk sammensetning, samt anvendelse derav. Disse polypeptidene og sammensetningene kan anvendes for behandling av gastrointestinale forstyrrelser.
BAKGRUNN
Foreliggende oppfinnelse angår polypeptid og farmasøytisk sammensetning, samt anvendelse derav. US 20040266989 beskriver også peptider, men de er forskjellige fra de i foreliggende oppfinnelse.
Irritabel tarm-syndrom (IBS) er en vanlig kronisk forstyrrelse i tarmen som rammer 20 til 60 million individer bare i USA (Lehman Brothers, Global Healthcare-lrritable bowel syndrome industry update, September 1999). IBS er den mest vanlige forstyrrelsen diagnostisert av gastroenterologer (28% av undersøkte pasienter) og står for 12% av besøkene hos leger innen primærhelsetjenesten (Camilleri 2001, Gastroenterology 120:652-668). I USA er den økonomiske innvirkningen av IBS anslått til 25 billioner US dollar årlig, gjennom direkte kostnader for bruk av helseomsorg og indirekte kostnader av arbeidsfravær (Talley 1995, Gastroenterology 109:1736-1741). Pasienter med IBS har tre ganger mer fravær
fra arbeid og melder om en redusert livskvalitet. De som lider av IBS kan være ute av stand til eller uvillige til å delta i sosiale hendelser, opprettholde arbeid, eller reise selv korte avstander (Drossman 1993, Dig Dis Sei 38:1569-1580). Det er et enormt udekket medisinsk behov i denne populasjonen siden det er få valgmuligheter med hensyn til medisiner for behandling av IBS.
Pasienter med IBS lider av abdominal smerte og et forstyrret mønster i tarmen.
Tre undergrupper av IBS-pasienter har blitt definert basert på fremherskende tendens med hensyn til tarmen: forstoppelsesdominert (c-IBS), diarédominert (d-IBS) eller vekslende mellom de to (a-IBS). Overslag av individer som lider av c-
IBS varierer fra 20-50% av IBS-pasientene hvor 30% ofte angis. Til forskjell fra de andre to undergruppene som har en lik kjønns-ratio, er c-IBS mer vanlig hos kvinner (ratio på 3:1) (Talley et al. 1995, Am J Epidemiol 142:76-83).
Definisjonen og de diagnostiske kriteriene for IBS har blitt formalisert i "Rome Criteria" (Drossman et al. 1999, Gut45:Suppl II: 1-81), som er velakseptert i klinisk praksis. Imidlertid har ikke kompleksiteten av symptomer blitt forklart ved anatomiske abnormiteter eller metabolske endringer. Dette har ført til klassifisering av IBS som en funksjonell Gl-forstyrrelse, som diagnostiseres på grunnlag av Rome-kriteriene og begrenset vurdering for å utelukke organisk sykdom. (Ringel et al. 2001, Annu Rev Med 52: 319-338). IBS er ansett for å være en "biopsykososial" forstyrrelse som følger som et resultat av en kombinasjon av tre interagerende mekanismer: endret motilitet av tarmen, en økt sensitivitet i tarmen eller colon for smertestimuli (visceral sensitivitet) og psykososiale faktorer (Camilleri 2001, Gastroenterology 120:652-668). I det siste har det vært økende belegg for at inflammasjon har en rolle i etiologien av IBS. Utredninger angir at undergrupper av IBS-pasienter har små men signifikante økninger i coloniske inflammatoriske og mastceller, økt induserbart nitrogenoksid (NO) og syntase (iNOS) og endret ekspresjon av inflammatoriske cytokiner (gjennomgått av Talley 2000, Medscape Coverage of DDW week).
OPPSUMMERING
Foreliggende oppfinnelse angår polypeptid og farmasøytisk sammensetning, samt anvendelse derav. Disse polypeptidene og sammensetningene kan anvendes for behandling av gastrointestinale forstyrrelser (for eksempel, irritabel tarmsyndrom, konstipasjon, en funksjonell gastrointestinal forstyrrelse, gastroesofagus reflukssykdom, funksjonell halsbrann, dyspepsi, gastroparese, kronisk intestinal pseudo-obstruksjon, kolon pseudo-obstruksjon, Chron's sykdom, ulcerativ kolitt og inflammatorisk tarmsykdom er beskrevet heri.
Forelligende oppfinnelse omfatter følgelig polypeptid, idet det består av aminosyresekvensen: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (Sekv.lD Nr:81)
eller et farmasøytisk akseptabelt salt derav. Polypeptid aktiverer guanylat cyklase C reseptoren.
Forelligende oppfinnelse omfatter videre farmasøytisk sammensetning som omfatter et polypeptid ifølge et hvilket som helst av kravene 1-2.
Forelligende oppfinnelse omfatter også anvendelse av et polypeptid ifølge et hvilket som helst av kravene 1-3, eller farmasøytisk sammensetning ifølge krav 3 for fremstilling av et medikament for behandling av en gastrointestinal forstyrrelse. Idet den gastrointestinale forstyrrelsen er en gastrointestinal bevegelsesforstyrrelse, og hvor den gastrointestinale forstyrrelsen er valgt fra gruppen bestående av: irritabel tarmsyndrom, konstipasjon, en funksjonell gastrointestinal forstyrrelse, gastroesofagus reflukssykdom, funksjonell halsbrann, dyspepsi, gastroparese, kronisk intestinal pseudo-obstruksjon, kolon pseudo-obstruksjon, Chron's sykdom, ulcerativ kolitt og inflammatorisk tarmsykdom. Konstipasjonen kan være kronisk konstipasjon, idiopatisk konstipasjon, grunnet postoperativ tarmslyng, eller forårsaket av opiatbruk.
Det irritable tarmsyndromet kan være alternerende irritabel tarmsyndrom eller konstipasjon-predominant irritabel tarmsyndrom.
Forelligende oppfinnelse omfatter også anvendelse av et polypeptid ifølge et hvilket som helst av kravene 1-2, eller den farmasøytiske sammensetningen ifølge krav 4 for fremstilling av et medikament for å øke den gastrointestinale motiliteten.
Forelligende oppfinnelse omfatter også anvendelse ifølge et hvilket som helst av kravene 4-11, hvor medikamentet administreres oralt.
Forelligende oppfinnelse omfatter også polypeptid ifølge kravene 1-2 eller farmasøytisk sammensetning ifølge krav 4, idet det er for behandling av en gastrointestinal forstyrrelse.
Forelligende oppfinnelse omfatter også polypeptid eller farmasøytisk sammensetning ifølge krav 13, idet den gastrointestinale forstyrrelsen er valgt fra gruppen bestående av: irritabel tarmsyndrom, konstipasjon, en funksjonell gastrointestinal forstyrrelse, gastroesofagus reflukssykdom, funksjonell halsbrann, dyspepsi, gastroparese, kronisk intestinal pseudo-obstruksjon, pseudo-obstruksjon, Chron's sykdom, ulcerativ kolitt og inflammatorisk tarmsykdom. Forelligende oppfinnelse omfatter også polypeptid eller farmasøytisk sammensetning ifølge krav 14, idet den gastrointestinale forstyrrelsen er konstipasjon.
Forelligende oppfinnelse omfatter også polypeptid eller farmasøytisk sammensetning ifølge krav 15, idet konstipasjonen er kronisk konstipasjon, idiopatisk konstipasjon, grunnet postoperativ tarmslyng eller forårsaket av opiatbruk.
Forelligende oppfinnelse omfatter også polypeptid eller farmasøytisk sammensetning ifølge krav 14, idet den gastrointestinale forstyrrelsen er irritabel tarmsyndrom.
Forelligende oppfinnelse omfatter også polypeptid eller farmasøytisk sammensetning ifølge krav 17, idet det irritable tarmsyndromet er alternerende irritabel tarmsyndrom eller konstipasjon-predominant irritabel tarmsyndrom.
Uten å være bundet av noen som helst bestemt teori, er peptidene i tilfellet av IBS og andre gastrointestinale forstyrrelser anvendelige fordi de kan forøke gastrointestinal motilitet.
Uten å være bundet av noen som helst bestemt teori, er peptidene i tilfellet av IBS og andre gastrointestinale forstyrrelser anvendelige, delvis, fordi de kan redusere inflammasjon.
Uten å være bundet av noen som helst bestemt teori, er peptidene i tilfellet av IBS og andre gastrointestinale forstyrrelser også anvendelige fordi de kan redusere gastrointestinal smerte eller visceral smerte.
Foreliggende oppfinnelse angår farmasøytiske blandinger omfattende bestemte peptider som er i stand til å aktivere guanylat syklase C (GC-C)-reseptoren. Oppfinnelsen omfatter også farmasøytiske blandinger omfattende et peptid eller GC-C-agonist ifølge oppfinnelsen og ett eller flere ytterligere terapeutiske midler omfattende, uten begrensning, midlene beskrevet heri. De andre midlene kan administreres sammen med peptidene ifølge oppfinnelsen (samtidig eller sekvensielt). De kan også bindes til et peptid ifølge oppfinnelsen for å danne terapeutiske konjugater.
Forskjellige gastrointestinale forstyrrelser kan behandles ved å administrere et peptid som virker som en delvis eller fullstendig agonist for GC-C-reseptoren. Peptidet omfatter minst seks cysteiner som kan danne tre disulfidbindinger. Disulfidbindingene kan erstattes av andre kovalente tverrbindinger og i noen tilfeller erstattes cysteinene med andre rester for å tillate alternative kovalente tverrbindinger. Peptidene kan også omfatte minst ett kløyvingssete for trypsin eller chymotrypsin og/eller et amino eller karboksyterminalt analgesisk peptid eller småmolekyl, for eksempel, AspPhe eller et annet analgesisk peptid. Når det er til stede i peptidet, kan et kløyvingssete for chymotrypsin eller trypsin være foran det analgesiske peptidet eller småmolekylet hvilket tillater frigivelse av det analgesiske peptidet eller småmolekylet. Peptidene ifølge foreliggende oppfinnelse er også anvendelige for behandling av smerte og inflammasjon forbundet med forskjellige forstyrrelser, omfattende gastrointestinale forstyrrelser. Visse peptider omfatter et funksjonelt kløyvingssete for chymotrypsin eller trypsin plassert slik at det tillater inaktivering av peptidet ved kløyving. Visse peptider som har et funksjonelt kløyvingssete gjennomgår kløyving og gradvis inaktivering i fordøyelseskanalen, og dette er ønskelig under noen omstendigheter. I visse peptider, er et funksjonelt sete for chymotrypsin endret, hvilket øker stabiliteten av peptidet in vivo.
Sammensetningene kan anvendes for å forøke intestinal motilitet. Intestinal motilitet omfatter spontane samordnede "dissentions" og sammentrekninger av magen, tarmene, colon og rektum for å føre mat gjennom magetarmkanalen under fordøyelsesprosessen.
Peptidene kan omfatte enten to eller flere sammenhengende negativt ladede aminosyrer (for eksempel Asp eller Glu) eller én eller to eller flere sammenhengende positivt ladede rester (for eksempel Lys eller Arg) eller én eller to eller flere sammenhengende positivt eller negativt ladede aminosyrer ved den karboksyterminale enden. I disse utførelsesformene er alle de flankerende aminosyrene ved den karboksyterminale enden enten positivt eller negativt ladet. I andre utførelsesformer er de karboksyterminale ladede aminosyrene innledet av en Leu. For eksempel kan hvilke som helst av de følgende aminosyresekvensene tilføyes til peptidets karboksyterminale ende: Asp; Asp Lys; Lys Lys Lys Lys Lys Lys; Asp Lys Lys Lys Lys Lys Lys; Leu Lys Lys; og Leu Asp. Det er også mulig å ganske enkelt tilføye Leu til den karboksyterminale enden.
En eller flere aminosyrer kan erstattes av en ikke-naturlig forekommende aminosyre eller en naturlig eller ikke-naturlig forekommende aminosyreanalog. Det finnes mange aminosyrer i tillegg til de standard 20. Noen er naturlig forekommende andre ikke (se, for eksempel, Hunt, The Non-Protein Amino Acids: I Chemistry and Biochemistry of the Amino Acids, Barrett, Chapman og Hall, 1985). For eksempel kan en aromatisk aminosyre erstattes med 3,4-dihydroksy-L-fenylalanin, 3-jodo-L-tyrosin, trijodotyronin, L-tyroxin, fenylglysin (Phg) eller nor-tyrosin (norTyr). Phg og norTyr og andre aminosyrer inkludert Phe og Tyr kan erstattes med, for eksempel, et halogen, -CH3, -OH, -CH2NH3, -C(0)H, -CH2CH3, - CN, -CH2CH2CH3, -SH eller en annen gruppe. Hvilken som helst aminosyre kan erstattes av D-formen av aminosyren.
Med hensyn til ikke-naturlig forekommende aminosyrer eller en naturlig og ikke-naturlig forekommende aminosyreanaloger, er mange forskjellige substitusjoner i peptidet ifølge formel I eller peptidet ifølge formel II mulig alene eller i kombinasjon.
Ytterligere eksempler på ikke-naturlige aminosyrer omfatter: en ikke-naturlig analog av tyrosin; en ikke-naturlig analog av glutamin; en ikke-naturlig analog av fenylalanin; en ikke-naturlig analog av serin; en ikke-naturlig analog av treonin; en alkyl, aryl, acyl, azido, cyano, halogen, hydrazin, hydrazid, hydroksyl, alkenyl, alkyni, eter, tiol, sulfonyl, seleno, ester, tiosyre, borat, boronat, fosfo, fosfono, fosfin, heterosyklisk grupe, enon, imin, aldehyd, hydroksylamin, keto eller aminosubstituert aminosyre, eller hvilken som helst kombinasjon derav; en aminosyre med en fotoaktiverbar tverrbindingsmiddel; en spinnmerket aminosyre; en fluorescerende aminosyre; en aminosyre med en ny funksjonell gruppe; en aminosyre som kovalent eller ikke-kovalent interagerer med et annet molekyl; en metallbindende aminosyre; en aminosyre som inneholder metall; en radioaktiv aminosyre; en photocaged og/eller fotoisomeriserbar aminosyre; en aminosyre inneholdende biotin eller biotinanalog; en glykosylert eller karbohydratmodifisert aminosyre; en keto-inneholdende aminosyre; aminosyrer omfattende polyetylenglykol eller polyeter; en aminosyre substituert med et tungt atom (for eksempel en aminosyre omfattende deuterium, tritium,13C,15N eller<18>0); en kjemisk kløyvbar eller fotokløyvbar aminosyre; en aminosyre med en forlenget sidekjede; en aminosyre inneholdende en toksisk gruppe; en sukkersubstituert aminosyre, for eksempel en sukkersubstituert serin eller lignende; en karbonbundet sukker-inneholdende aminosyre; en redoksaktiv aminosyre; en o> hydroksy-inneholdende syre; en aminotiosyre inneholdende aminosyre; en a,o> disubstituert aminosyre; en p-aminosyre; en syklisk aminosyre andre enn prolin; en O-metyl-L-tyrosin; en L-3-(2-naftyl)alanin; en 3-metyl-fenylalanin; en p-acetyl-L-fenylalanin; en 0-4-allyl-L-tyrosin; en 4-propyl-L-tyrosin; en tri-O-acetyl-GIcNAcP-serin; en L-Dopa; en fluor fenylalanin; en isopropyl-L-fenylalanin; en p-azido-L-fenylalanin; en p-acyl-L-fenylalanin; en p-benzoyl-L-fenylalanin; en L-fosfoserin; en fosfonoserin; en fosfonotyrosin; en p-jodo-fenylalanin; et 4-fluorfenylglysin; en p-bromfenylalanin; en p-amino-L-fenylalanin; en isopropyl-L-fenylalanin; L-3-(2-naftyl)alanin; en amino-, isopropyl-, eller O-allyl-inneholdende fenylalaninanalog; en dopa, O-metyl-L-tyrosin; en glykosylert aminosyre; en p-(propargyloksy)fenylalanin; dimetyl-Lysin; hydroksyprolin; merkaptopropionsyre; metyl-lysin; 3-nitro-tyrosin; norleucin; pyro-glutaminsyre; Z (karbobenzoksyl); e-Acetyl-Lysin; (3-alanin; aminobenzoylderivat; aminosmørsyre (Abu); citrullin; aminohexanoic acid; aminoisosmørsyre; sykloheksylalanin; d-sykloheksylalanin; hydroksyprolin; nitro-arginin; nitro-fenylalanin; nitro-tyrosin; norvalin; oktahydroindol-karboksylat; ornitin; penicillamin; tetrahydroisoquinolin; acetamidometyl-beskyttede aminosyrer og pegylerte aminosyrer. Ytterligere eksempler på ikke-naturlige aminosyrer og aminosyreanaloger kan finnes i U.S. 20030108885, U.S. 20030082575 og referansene anført deri.
En aminosyre kan erstattes av en naturlig forekommende, ikke-essensiell aminosyre, for eksempel taurin.
Metoder for fremstilling av peptider som inneholder ikke-naturlige aminosyrer kan finnes i, for eksempel, U.S. 20030108885, U.S. 20030082575, Deiters et al., J Am Chem Soc. (2003) 125:11782-3, Chin et al., Science (2003) 301:964-7, og referansene omtalt deri.
Peptider som omfatter ikke-naturlige aminosyrer kan også fremstilles ved anvendelse av metodene beskrevet i WO02086075.
Peptidene kan ha én eller flere konvensjonelle peptidbindinger erstattet av en alternativ binding. Slike erstatninger kan øke stabiliteten av peptidet. For eksempel kan en erstatning av peptidbindingen mellom Cysisog Xaaig med en alternativ binding redusere kløyving ved karboksypeptidaser og kan øke halveringstiden i fordøyelseskanalen. Bindinger som kan erstatte peptidbindinger omfatter: en retro-inverso-binding (C(O)-NH i stedet for NH-C(O); en redusert amidbinding (NH-CH2); en thiometylenbinding (S-CH2eller CH2-S); en oksometylenbinding (0-CH2eller CH2-0); en etylenbinding (CH2-CH2); en tioamidbinding (C(S)-NH); en trans-olefinbinding (CH=CH); en fluorsubstituert trans-olefinbinding (CF=CH); en ketometylenbinding (C(O)-CHR eller CHR-C(O) hvori R er H eller CH3; og en fluor-ketometylenbinding (C(O)-CFR eller CFR-C(O) hvori R er H eller F eller CH3.
Peptidene kan modifiseres ved anvendelse av standard modifikasjoner. Modifikasjoner kan forekomme ved den amino (N-), karboksy (C-)-terminale enden, internt eller en kombinasjon av hvilke som som helst av de foregående. I ett aspekt av oppfinnelsen kan det være mer enn én type modifikasjon av peptidet. Modifikasjoner omfatter men er ikke begrenset til: acetylering, amidering, biotinylering, cinnamoylation, farnesylering, formylering, myristoylering, palmitoylering, fosforylering (Ser, Tyr eller Thr), stearoylation, succinylering, sulfurylation og syklisering (via disulfidbruer eller amid syklisering), og modifikasjon ved Cy3 eller Cy5. Peptidene kan også modifiseres ved 2,4-dinitrofenyl (DNP), DNP-lysin, modifikasjon ved 7-Amino-4- metyl-kumarin (AMC), flourescein, NBD (7-Nitrobenz-2-oksa-1,3-Diazol), p-nitro-anilid, rhodamin B, EDANS (5-((2-aminoetyl)amino) naftalen-1-sulfon ("sulfonic")syre), dabcyl, dabsyl, dansyl, texas red, FMOC og Tamra (Tetrametylrhodamin). Peptidene ifølge oppfinnelsen kan også konjugeres til, for eksempel, polyetylenglykol (PEG); alkylgrupper (for eksempel C1-C20 rette eller forgrenede alkylgrupper); fettsyreradikaler; kombinasjoner av PEG, alkylgrupper og fettsyreradikaler (se U.S. Patent 6,309,633; Soltero et al., 2001 Innovations in Pharmaceutical Technology 106-110); BSA og KLH (Keyhole Limpet Hemocyanin).
Peptidene og agonistene kan modifiseres kjemisk for å øke terapeutisk aktivitet ved å tilføye sukkergrupper syntetisk (WO88/02756; WO 89/09786; DE 3910667A1, EP 0 374 089 A2; og U.S. 4,861,755), tilsette kationiske forankringsgrupper (EP0363589), lipidgrupper (WO91/09837; U.S. 4,837,303) eller substituentene beskrevet som forbindelsene I, II og III i US5552520.
Det er noen sekvenslikheter med ST-peptider. Imidlertid omfatter de aminosyreendringer og/eller tilføyelser som forbedrer funksjonalitet. Disse endringene kan, for eksempel, øke eller redusere aktivitet (for eksempel øke eller redusere peptidets evne til å stimulere intestinal motilitet), endre peptidets evne til å foldes korrekt, endre peptidets stabilitet, endre peptidets evne til å binde til GC-C-reseptoren og/eller redusere toksisitet. I noen tilfeller kan peptidene fungere mer ønskelig enn villtype ST-peptid. For eksempel kan de begrense uønskelige bivirkninger slik som diaré og dehydrering.
I tillegg kan én eller flere disulfidbindinger erstattes av alternative kovalente tverrbindinger, for eksempel en amidbinding (-CH2CH(0)NHCH2- eller - CH2NHCH(0)CH2-), en esterbinding, en tioesterbinding, en laktam-bro, karbamoylbinding, en ureabinding, en tioureabinding, en fosfonat-esterbinding, en alkylbinding (-CH2CH2CH2CH2-), en alkenylbinding, (-CH2CH=CHCH2-), en eterbinding (-CH2CH2OCH2- eller -CH2OCH2CH2-), en tioeterbinding (-CH2CH2SCH2- eller -CH2SCH2CH2-), en aminbinding (-CH2CH2NHCH2- eller-CH2NHCH2CH2-) eller en tioamidbinding (-CH2CH(S)HNHCH2- eller - CH2NHCH(S)CH2-). For eksempel beskriver Ledu et al. (Proceedings Nafl Acad. Sei. 100:11263-78, 2003) fremgangsmåter for fremstilling av laktam og amid-tverrbindinger. Schafmeister et al. (J. Am. Chem. Soc. 122:5891, 2000) beskriver stabile, rene karbon-tverrbindinger. Hydrokarbon-tverrbindinger kan frembringes ved metatese (eller metatese etterfulgt av hydrering i tilfelle av mettede hydrokarbon-tverrbindinger) ved anvendelse av en eller annen av Grubbs katalysatorer (tilgjengelig fra Materia, Inc. og Sigma-Aldrich og beskrevet, for eksempel, i U.S. Patenter Nr. 5,831,108 og 6,111,121). I noen tilfeller krever frembringelse av slike alternative kryssbindinger erstatning av Cys-restene med andre rester slik som Lys eller Glu eller ikke-naturlig forekommende aminosyrer. I tillgg kan laktam, amid og hydrokarbon-tverrbindinger anvendes for å stabilisere peptidet selv om de forbinder aminosyrer ved posisjoner andre enn de som inntas av Cys. Slike tverrbindinger kan forekomme mellom to aminosyrer som er adskilt av to aminosyrer eller mellom to aminosyrer som er adskilt av seks aminosyrer (se, for eksempel, Schafmeister et al. (J. Am. Chem. Soc. 122:5891, 2000)).
Peptidene kan administreres sammen med eller bindes, for eksempel, bindes kovalent til hvilket som helst av mange forskjellige andre peptider inkludert analgesiske peptider eller analgesiske forbindelser omfattende, uten begrensning, midlene beskrevet heri.
Aminosyre, ikke-aminosyre, peptid og ikke-peptid-spacere kan anbringes mellom et peptid som er en GC-C-reseptoragonist og et peptid som har en annen biologisk funksjon, for eksempel, et analgesisk peptid eller et peptid anvendt for å behandle fedme. Linkeren kan være en som kløyves fra de flankerende peptidene in vivo eller en som forblir bundet til de flankerende peptidene in vivo. For eksempel kan glysin, beta-alanin, glysyl-glysin, glysyl-beta-alanin, gamma-aminosmørsyre, 6-aminokapronsyre, L-fenylalanin, L-tryptofan og glycil-L-valil-L-fenylalanin anvendes som spacere (Chaltin et al. 2003 Helvetica Chimica Acta 86:533-547; Caliceti et al. 1993 FARMCO 48:919-32) i likhet med polyetylenglykoler (Butterworth et al. 1987 J. Med. Chem 30:1295-302) og maleimid-derivater (King et al. 2002 Tetrahedron Lett. 43:1987-1990). Forskjellige andre linkere er beskrevet i litteraturen (Nestler 1996 Molecular Diversity 2:35-42; Finn et al. 1984 Biochemistry 23:2554-8; Cook et al. 1994 Tetrahedron Lett. 35:6777-80; Brokx et al. 2002 Journal of Controlled Release 78:115-123; Griffin et al. 2003 J. Am. Chem. Soc. 125:6517-6531; Robinson et al. 1998 Proe. Nati. Acad. Sei. USA 95:5929-5934).
Peptidene kan være bundet til én, to eller flere forskjellige grupper som hver tilveiebringer like eller forskjellige funksjoner. For eksempel kan peptidet bindes til et molekyl som er et analgetikum og til et peptid som anvendes for å behandle fedme. Peptidet og forskjellige grupper kan være ordnet på forskjellige måter. For eksempel kan et peptid ifølge oppfinnelsen ha et analgesisk peptid bundet til dets aminoterminale ende og et anti-fedme-peptid bundet til dets karboksyterminale ende. De ytterligere gruppene kan være direkte kovalent bundet til peptidet eller kan være bundet via linkere.
Peptidet kan være et syklisk peptid eller et lineært peptid. I tillegg, kan multiple kopier av det samme peptidet inkorporeres inn i et enkelt syklisk eller lineært peptid.
Peptidene kan omfatte aminosyresekvensen av et peptid som forekommer naturlig i en virveldyr (for eksempel pattedyreart eller i en bakterieart. I tillegg kan peptidene være delvis eller fullstendig ikke-naturlig forekommende peptider.
I forskjellige utførelsesformer lider pasienten av en gastrointestinale forstyrrelse; pasienten lider av en forstyrrelse valgt fra gruppen bestående av: gastrointestinale motilitetsforstyrrelser, kronisk intestinal pseudoobstruksjon, colonisk pseudoobstruksjon, Crohns sykdom, duodenogastrisk refluks, dyspepsi, funksjonell dyspepsi, non-ulcer dyspepsi, en funksjonell gastrointestinal forstyrrelse, funksjonell kardialgi, gastroøsofagal reflukssykdom (GERD), gastroparese, irritabel tarm-syndrom, postoperativ ileus, colitis ulcerosa, kronisk konstipasjon og forstyrrelser og tilstander forbundet med konstipasjon (for eksempel er konstipasjon forbundet med anvendelse av opiumsholdige smertestillende midler, post-kirurgisk konstipasjon og konstipasjon forbundet med neuropatiske lidelser så vel som andre tilstander og forstyrrelser beskrevet heri); pasienten lider av gastrointestinale motilitetsforstyrrelser, kronisk intestinal pseudoobstruksjon, colonisk pseudoobstruksjon, Crohns sykdom, duodenogastrisk refluks, dyspepsi, funksjonell dyspepsi, non-ulcer dyspepsi, en funksjonell gastrointestinal forstyrrelse, funksjonell kardialgi, gastroøsofagal reflukssykdom (GERD), gastroparese, inflammatorisk tarmsykdom, irritabel tarm-syndrom, postoperativ ileus, colitis ulcerosa, kronisk konstipasjon og forstyrrelser og tilstander forbundet med konstipasjon (for eksempel er konstipasjon forbundet med anvendelse av opiumsholdige smertestillende midler, post-kirurgisk konstipasjon og konstipasjon forbundet med neuropatiske lidelser så vel som andre tilstander og forstyrrelser beskrevet heri); sammensetningen administreres oralt.
Pasienter som lider av konstipasjon kan behandles. Klinisk aksepterte kriterier som definerer konstipasjon varierer fra hyppigheten av avføring, konsistensen av feces og bekvemmeligheten av avføring. En felles definisjon på konstipasjon er mindre enn tre avføringer pr. uke. Andre definisjoner omfatter unormalt hard avføring eller avføring som krever urimelig anstrengelse (Schiller 2001, Aliment Pharmacol Ther 15:749-763). Konstipasjon kan være idiopatisk (funksjonell konstipasjon eller "slow transit" konstipasjon) eller sekundær til andre årsaker inkludert neurologiske, metabolske eller endokrine lidelser. Disse lidelsene omfatter diabetes mellitus, hypotyroidisme, hypertyroidisme, hypokalsemi, multippel sklerose, Parkinsons sykdom, ryggmargskader, neurofibromatose, autonom neuropati, Chagas sykdom, Hirschsprungs sykdom og cystisk fibrose. Konstipasjon kan også være resultatet av kirurgi (postoperativ ileus) eller skyldes anvendelse av medikamenter slik som analgetika (som opioder), antihypertensiva, anticonvulsiva, antidepressiva, krampestillende midler og antipsykotiske midler.
I forskjellige utførelsesformer er konstipasjonen forbundet med anvendelse av et terapeutisk middel; konstipasjonen er forbundet med en neuropatisk forstyrrelse; konstipasjonen er post-kirurgisk konstipasjon (postoperativ ileus); og konstipasjonen er forbundet med en gastrointestinal forstyrrelse; konstipasjonen er idiopatisk (funksjonell konstipasjon eller "slow transit" konstipasjon); konstipasjonen er forbundet med neuropatisk, metabolsk eller endokrin forstyrrelse (for eksempel diabetes mellitus, hypotyroidisme, hypertyroidisme, hypokalsemi, multippel sklerose, Parkinsons sykdom, rykkmargskader, neurofibromatose, autonom neuropati, Chagas sykdom, Hirschsprungs sykdom eller cystisk fibrose). Konstipasjon kan også være resultatet av kirurgi (postoperativ ileus) eller skyldes anvendelse av medikamenter slik som analgetika (for eksempel opioder), antihypertensiva, antikonvulsiva, antidepressiva, krampestillende midler og antipsykotiske midler.
Pasienten kan lide av en gastrointestinal forstyrrelse; pasienten lider av en forstyrrelse valgt fra gruppen bestående av: gastrointestinale motilitetsforstyrrelser, kronisk intestinal pseudoobstruksjon, colonisk pseudoobstruksjon, Crohns sykdom, duodenogastrisk refluks, dyspepsi, funksjonell dyspepsi, non-ulcer dyspepsi, en funksjonell gastrointestinal forstyrrelse, funksjonell kardialgi, gastroøsofagal reflukssykdom (GERD), gastroparese, irritabel tarm-syndrom, postoperativ ileus, colitis ulcerosa, kronisk konstipasjon og forstyrrelser og tilstander forbundet med konstipasjon (for eksempel er konstipasjon forbundet med anvendelse av opiumsholdige smertestillende midler, post-kirurgisk konstipasjon og konstipasjon forbundet med neuropatiske lidelser så vel som andre tilstander og forstyrrelser beskrevet heri), fedme, kongestiv hjertesvikt eller hypertrophia prostatae.
Det er mulig å øke aktiviteten av (aktivere) en intestinal guanylat syklase (GC-C)-reseptor hos en pasient, ved å administrere til en pasient et peptid ifølge oppfinnelsen.
Peptidet kan administreres i kombinasjon med ett eller flere agenser for behandling av kongestiv hjertesvikt, for eksempel, et natriuretisk peptid slik som atrial natriuretisk peptid, hjerne natriuretisk peptid eller C-type natriuretisk peptid), et diuretikum eller en inhibitor for angiotensinomdannende enzym.
Agonisten kan administreres alene eller i kombinasjon med et annet agens for behandling av kongestiv hjertesvikt, for eksempel et natriuretisk peptid slik som atrial natriuretisk peptid, hjerne natriuretisk peptid eller C-type natriuretisk peptid, et diuretikum eller en inhibitor for angiotensinomdannende enzym.
Isolerte nukleinsyremolekyler kan omfatte en sekvens som koder for et peptid ifølge oppfinnelsen. Vektorer, for eksempel, ekspresjonsvektorer kan omfatte slike nukleinsyremolekyler og kan anvendes for å uttrykke et peptid ifølge oppfinnelsen i en dyrket celle (for eksempel en eukaryot celle eller en prokaryot celle). Vektoren kan videre omfatte ett eller flere regulatoriske elementer, for eksempel en heterolog promoter eller elementer nødvendige for translasjon operabelt bundet til sekvensen som koder for peptidet. I noen tilfeller vil nukleinsyremolekylet kode for en aminosyresekvens som omfatter aminosyresekvensen av et peptid ifølge oppfinnelsen. For eksempel kan nukleinsyremolekylet kode for et preprotein eller et preproprotein som kan prosesseres for å frembringe et peptid ifølge oppfinnelsen.
En vektor som omfatter en nukleotidsekvens som koder for et peptid ifølge oppfinnelsen eller et peptid eller polypeptid omfattende et peptid ifølge oppfinnelsen kan være enten RNA eller DNA, enkelt- eller dobbelttrådet, prokaryot, eukaryot eller viralt. Vektorer kan omfatte transposoner, virale vektorer, episomer, (for eksempel plasmider), kromosom inserts, og kunstige kromosomer (for eksempel BAC eller YAC). Egnede bakterieverter for ekspresjon av det kodede peptidet eller polypeptidet omfatter, men er ikke begrenset til, E. coli. Egnede eukaryote verter omfatter gjær slik som S. cerevisiae, annen sopp, celler fra virveldyr, celler fra virvelløse dyr (for eksempel insektceller), planteceller, humane celler, humane vevsceller og hele eukaryote organismer, (for eksempel en transgen plante eller et transgent dyr). Videre kan nukleinsyre-vektoren anvendes for å transfektere et virus slik som vaccinia eller baculovirus (for eksempel ved anvendelse av Bac-to-Bac® Baculovirus ekspresjonssystemet (Invitrogen Life Technologies, Carlsbad, CA)).
Vektorer og genetiske konstruksjoner egnet for fremstilling av et peptid ifølge oppfinnelsen eller et peptid eller polypeptid omfattende et slikt peptid kan også omfatte den genetiske konstruksjonen, og i tillegg til det kodende nukleinsyremolekylet, elementer som muliggjør ekspresjon, slik som en promoter og reguleringssekvenser. Ekspresjonsvektorene kan omfatte transkripsjonskontrollsekvenser som styrer initiering av transkripsjon, slik som promoter, enhancer, operator og repressorsekvenser. Mange forskjellige transkripsjonskontrollsekvenser er velkjente for fagfolk på området og kan være funksjonelle i, men er ikke begrenset til, en bakterie, gjær, plante eller dyrecelle. Ekspresjonsvektoren kan også omfatte en reguleringssekvens for translasjon (for eksempel en utranslatert 5'-sekvens, en utranslatert 3'-sekvens, et sete for tilføyelse av poly A, eller et indre ribosombindingssete), en splicingsekvens eller splicing reguleringssekvens, og en transkripsjonstermineringssekvens. Vektoren kan være i stand til autonom replikasjon eller den kan integrere inn i verts-DNA. Isolerte vertsceller kan omfatte én av de førnevnte nukleinsyremolekylene og fremstille et peptid ved å dyrke en slik celle og utvinne peptidet eller en forløper av peptidet. Utvinning av peptidet eller forløpere kan referere til å oppsamle dyrkingsløsningen og behøver ikke å omfatte ytterligere rensningstrinn. Proteiner ifølge foreliggende oppfinnelse kan, imidlertid, renses ved anvendelse av standard rensningsteknikker, slik som, men ikke begrenset til, affinitetskromatografi, thermaprecipitation, immunoaffinitetskromatografi, ammoniumsulfat presipitering, ionebytterkromatografi, filtrering, elektroforese og hydrofob interaksjons kromatografi.
Peptidene kan renses. Rensede peptider er peptider separert fra andre proteiner, lipider og nukleinsyrer eller fra forbindelsene fra hvilke de er syntetisert. Polypeptidet kan utgjøre minst 10, 20, 50 70, 80 eller 95% med hensyn til tørrvekt av det rensede preparatet.
Blant de anvendelige peptidene er peptider omfattende, bestående av, eller bestående hovedsakelig av aminosyresekvensen XaaiXaa2Xaa3Xaa4Xaa5Cys Cys Glu Xaa9Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr Xaa2oXaa2i(II) (SEKV ID NR:--) er de følgende peptidene:
Også anvendelige er peptider som omfatter, består av eller består hovedsakelig av hvilke som helst av de følgende sekvensene:
Delesjonsvarianter kan oppstå av hvilke som helst av peptidene beskrevet heri hvor én, to, tre eller fire aminosyrer (eller ikke-naturlige aminosyrer eller naturlig eller ikke-naturlige aminosyreanaloger), andre enn en Cys (eller en aminosyre som erstatter Cys, for eksempel en aminosyre i stand til å danne en kovalent binding med en annen aminosyre), er deletert. Når to (eller flere) aminosyrer er deletert og peptidet omfatter sekvensen: CysaCysbXaa Xaa CyscCysdXaa Xaa Xaa CyseXaa Xaa Cysf, kan, i noen utførelsesformer, to eller flere delesjoner være lokalisert mellom Cysbog Cyscog/eller mellom Cysdog Cyseog/eller mellom
Cyseog Cysf. Imidlertid er det i det meste én delesjon mellom hver av Cysbog Cysceller mellom Cysdog Cyseeller mellom Cyseog Cysf. Peptidene beskrevet
heri kan omfatte sekvensen CysaCysbXaa Xaa CyscCysdXaa Xaa Xaa CyseXaa Xaa Cysfhvori: a) én aminosyre mellom Cysbog Cyscer deletert; b) én aminosyre mellom Cysdog Cyseer deletert; c) én aminosyre mellom Cyseog Cysfer deletert;
d) én aminosyre mellom Cysbog Cyscer deletert og én aminosyre mellom Cysdog Cyseer deletert; e) én aminosyre mellom Cysdog Cyseer deletert og én
aminosyre mellom Cyseog Cysfer deletert; f) én aminosyre mellom Cysbog Cyscer deletert og én aminosyre mellom Cyseog Cysfer deletert eller g) én aminosyre mellom Cysbog Cyscer deletert, én aminosyre mellom Cysdog Cyseer deletert og én aminosyre mellom Cyseog Cysfer deletert. De forskjellige delesjonsvariantene er peptider som binder til og/eller aktiverer GC-C-reseptoren. De forskjellige delesjonsvariantene er peptider som øker nivåene av cGMP.
Delesjonvarianter av Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:3) omfatter peptidene listet opp i FIG. 11.1 disse delesjonsvariantene, kan hvilke som helst av aminosyrene være deletert og én, to, tre eller fire aminosyrer andre enn Cys kan være deletert.
Insersjonsvarianter av hvilke som helst av peptidene beskrevet heri kan dannes
hvor én, to, tre eller fire aminosyrer (for eksempel Gly eller Ala) er insertert før eller etter hvilken som helst aminosyre i peptidet. Ikke mer enn én aminosyre kan noen ganger være insertert mellom to Cys. For eksempel når to eller flere aminosyrer er insertert og peptidet omfatter sekvensen CysaCysbXaa Xaa CyscCysdXaa Xaa Xaa CyseXaa Xaa Cyst, kan to eller flere insersjoner være lokalisert mellom Cysbog Cysceller mellom Cysdog Cyseeller mellom Cyseog Cysf. Imidlertid kan det være at ikke mer enn én insersjon er lokalisert mellom Cysbog Cysceller mellom Cysdog Cyseeller mellom Cyseog Cysf. Peptidene beskrevet heri kan følgelig omfatte sekvensen CysaCysbXaa Xaa CyscCysdXaa Xaa Xaa CyseXaa Xaa Cysfhvori: a) én aminosyre er insertert mellom Cysbog Cysc; b) én aminosyre er insertert mellom Cysdog Cyse; c) én aminosyre er insertert mellom Cyseog Cyst;
d) én aminosyre er insertert mellom Cysbog Cyscog én aminosyre er insertert mellom Cysdog Cyse; e) én aminosyre er insertert mellom Cysdog Cyseog én
aminosyre er insertert mellom Cyseog Cyst; f) én aminosyre er insertert mellom
Cysbog Cyscog én aminosyre er insertert mellom Cyseog Cyst; eller g) én aminosyre er insertert mellom Cysbog Cysc, én aminosyre er insertert mellom Cysdog Cyseog én aminosyre er insertert mellom Cyseog Cysf. I tillegg kan én eller flere aminosyrer være insertert foran Cysaog/eller én eller flere aminosyrer kan være insertert etter Cysf.
I forskjellige tilfeller er de forskjellige insersjonsvariantene peptider som binder til og/eller aktiverer GC-C-reseptoren. I forskjellige tilfeller er de forskjellige insersjonsvariantene peptider som forøker nivåer av cGMP.
Insersjonsvarianter av Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:3) omfatter slike hvor opptil fire aminosyrer (dvs. 0, 1, 2, 3 eller 4) kan være insertert etter hver aminosyre. Følgelig peptider som har sekvensen: CysXaa(o-4) CysXaa(o-4) Glu Xaa(o-4>Tyr Xaa(o-4>Cys Xaa(o-4>Cys Xaa(o-4>Asn Xaa(o-4) Pro Xaa(0-4) Ala Xaa(0-4) Cys Xaa(0-4) Thr Xaa(0-4) Gly Xaa(0-4) Cys Xaa(0-4) Tyr Xaa(o-4) (SEKV ID NR:). De inserterte aminosyrene kan være hvilken som helst aminosyre eller aminosyreanalog (naturlig eller ikke-naturlig) og kan være like eller forskjellige. I visse former er alle de inserterte aminosyrene Gly eller alle Ala eller en kombinasjon av Gly og Ala.
FIG. 12 viser insersjonsvarianter av peptidet som har sekvensen: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:3).
Det er også beskrevet varianter av peptider som har sekvensen XaaiXaa2Xaa3Xaa4Xaa5Cys6CyszXaasXaag CysioCysnXaai2Xaai3Xaai4Cysi5Xaai6Xaau CysisXaai9Xaa2oXaa2i(SEKV ID NR:1), for eksempel varianter av Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:3), hvor opptil fire aminosyrer er deletert og/eller opptil fire aminosyrer er insertert. Insersjonene og delesjonene kan være mellom Cys6og Cysisi SEKV ID NR:1 eller de kan være aminoterminale for Cys6og/eller karboksyterminale for Cys^ i SEKV ID NR:1.
Peptidene kan også omfatte én eller flere av peptid-modifikasjonene, én eller flere ikke-naturlige aminosyrer eller aminosyreanaloger, én eller flere av alternativene for disulfidbinding eller én eller flere av de alternative peptidbindingene beskrevet heri.
Peptidene ifølge oppfinnelsen kan være til stede med et motion. Anvendelige motioner omfatter salter av: acetat, benzensulfonat, benzoat, kalsium-edetat, camsylate, karbonat, citrat, edetat (EDTA), edisylat, embonat, esylat, fumarat, gluceptat, glukonat, glutamat, glykollylarsanilat, heksylresorcinat, jodid, bromid, klorid, hydroksynafoat, isetionat, laktat, laktobionat, estolat, maleat, malat, mandelat, mesylat, mucate, napsylat, nitrat, pantotenat, fosfat, salicylat, stearat, succinat, sulfat, tartarat, teoclat, acetamidobenzoat, adipat, alginat, aminosalicylat, anhydrometylencitrat, ascorbat, aspartat, camphorate, caprate, caproate, kaprylat, cinnamat, syklamat, dikloracetat, format, gentisat, glukuronat, glyserofosfat, glykolat, hippurat, fluorid, malonat, napadisylat, nikotinat, oleat, orotat, oksalat, oksoglutarat, palmitat, pectinat, pectinatpolymer, fenyletylbarbiturat, picrat, propionat, pidolat, sebakat, rhodanid, tosylat og tannat.
Peptidene og agonisten for intestinal guanylat syklase (GC-C)-reseptoren kan anvendes for å behandle konstipasjon eller redusert intestinal motilitet, langsom fordøyelse eller langsom magetømming. Peptidene kan anvendes for å lindre ett eller flere symptomer på IBS (oppblåsthet, smerte, konstipasjon), GERD (syrerefluks inn i øsofagus), duodenogastrisk refluks, funksjonell dyspepsi eller gastroparese (kvalme, oppkasting, oppblåsthet, forsinket magetømming) og andre forstyrrelser beskrevet heri.
Detaljene for én eller flere utførelsesformer ifølge oppfinnelsen er vist i den ledsagende beskrivelsen.
FIGURER
Figur 1 viser resultatene av LCMS-analyse av rekombinant peptid ifølge SEKV ID NR:4 og SEKV ID NR:5. Figurene 1 b og 1c viser resultatene av LCMS-analyse av syntetisk SEKV ID NR: 3-peptid og blankprøven. Figur 2 viser resultatene av intestinal GC-C-reseptor-aktivitetsanalyse av syntetisk SEKV ID NR:4-peptid, SEKV ID NR:5-peptid og to ulike SEKV ID NR:3-peptider. Figur 3a viser effekten av rekombinant SEKV ID NR:4-peptid og Zelnorm® i en akutt murin gastrointestinal transitt-modell. Figur 3b viser effekten av syntetisk SEKV ID NR:3-peptid og Zelnorm® i en akutt murin gastrointestinal transitt-modell. Figurene 4a og 4b viser effekten av peptidene SEKV ID NR:5, SEKV ID NR:3, og SEKV ID NR:4 i en akutt murin gastrointestinal transitt-modell. Figur 4c viser effekten av peptid ifølge SEKV ID NR:3 i en kronisk murin gastrointestinal transitt-modell. Figur 5a viser effekten av peptid ifølge SEKV ID NR:4 og Zelnorm® i en nyfødt mus intestinal sekresjonsmodell. Figur 5b viser effektene av SEKV ID NR:3 og Zelnorm® i en mus intestinal sekresjonsmodell. Figurene 6a og 6b viser effektene av SEKV ID NR:4, SEKV ID NR:3 og SEKV ID NR:5-peptider i en musemodell av intestinal sekresjon. Figur 7 viser resultatene av eksperiment hvor SEKV ID NR:3-aktivitet ble anlysert i TNBS colon distensjon-modellen. Figurene 8a og 8b viser effektene av forskjellige doser av SEKV ID NR:5 og SEKV ID NR:3 i PBQ vridningsanalysen. Figur 9 viser resultatene av Kd bestemmelsesanalyse ved anvendelse av SEKV ID NR:3 i en kompetitiv radioligandbindingsanalyse. Figurene 10a og 10b viser biotilgjengelighetsdata for IV og oralt administrert SEKV ID NR:3 som detektert ved en ELISA-analyse og LCMS. Figur 11 viser delesjonsvarianter av et peptid som har sekvensen ifølge SEKV ID NR:3. Figur 12 viser insersjonsvarianter av et peptid som har sekvensen ifølge SEKV ID NR:3.
DETALJERT BESKRIVELSE
Peptidene ifølge oppfinnelsen binder til intestinal guanylat syklase (GC-C)-reseptoren, en viktig regulator for væske og elektrolyttbalanse i tarmen. Når den stimuleres bevirker denne reseptoren, som er lokalisert på apikalmembranen på overflaten av tarmepitel, en økning i tarmepitel syklisk GMP (cGMP). Denne økningen i cGMP er antatt å bevirke en redusert absorpsjon av vann og natrium og en økning i sekresjon av klorid og kaliumioner, hvilket fører til endringer i væske og elektrolytt-transport i tarmen og økt intestinal motilitet. Den intestinale GC-C-reseptoren har en ekstracellulær ligandbindende region, en transmembranregion, en intracellulær protein kinase-lignende region og et syklase katalystisk domene. Foreslåtte funksjoner for GC-C-reseptoren er væske og elektrolytt homeostase, regulering av epitelcelle proliferasjon og induksjon av apoptose (Shalubhai 2002 Curr Opin Drug Dis Devel 5:261-268).
I tillegg til at den uttrykkes i tarmen av gastrointestinale epitelceller, blir GC-C uttrykt i ekstra-intestinale vev inkludert nyre, lunge, pankreas, hypofyse, binyre, lever under utvikling og galleblære (oversikt ved Vaandrager 2002 Mol Cell Biochem 230:73-83, Kulaksiz et al. 2004, Gastroenterology 126:732-740) og mannlig og kvinnelig reproduktivt vev (oversikt ved Vaandrager 2002 Mol Cell Biochem 230:73-83). Dette antyder at GC-C-reseptor-agonistene kan anvendes ved behandling av forstyrrelser utenfor magetarm-kanalen, for eksempel, kongestiv hjertesvikt og hypertrophia prostatae.
Ghrelin, et peptidhormon sekretert av magen, er en viktig regulator for apetitt hos mennesker. Ekspresjonsnivåer av ghrelin reguleres ved fasting og ved magetømming (Kim et al. 2003 Neuroreprt 14:1317-20; Gualillo et al. 2003 FEBS Letts 552:105-9). Ved å øke gastrointestinal motilitet, kan følgelig GC-C reseptoragonister også anvendes for å regulere fedme.
Hos mennesker blir GC-C-reseptoren aktivert av guanylin (Gn) (U.S. 5,96,097), uroguanylin (Ugn) (U.S. 5,140,102) og lymphoguanylin (Forte et al. 1999 Endocrinology 140:1800-1806). Interessant nok er disse midlene 10-100 ganger mindre potente enn en klasse av bakterielt avledede peptider, betegnet ST (oversikt i Gianella 1995 J Lab Clin Med 125:173-181). ST-peptider anses som superagonister for GC-C og er svært resistente mot proteolytisk degradering.
ST-peptid er i stand til å stimulere det enteriske nervesystemet (Rolfe et al., 1994, J Physiolo 475:531-537; Rolfe et al. 1999 Gut 44:615-619; Nzegwu et al. 1996 Exp Physiol 81:313-315). Likeså har cGMP blitt angitt å ha antinociceptive effekter i mangfoldige dyremodeller for smerte (Lazaro Ibanez et al. 2001 Eur J Pharmacol 426:39-44; Soares et al. 2001 British J Pharmacol 134:127-131; Jain et al. 2001 Brain Res 909:170-178; Amarante et al. 2002 Eur J Pharmacol 454:19-23). Følgelig kan GC-C-agonister ha både en analgesisk så vel som en anti-inflammatorisk effekt.
Hos bakterier er ST-peptider avledet fra et preproprotein som generelt har minst 70 aminosyrer. Pre og pro-regionene kløyves som del av sekresjonsprosessen, og det resulterende modne proteinet, som generelt omfatter færre enn 20 aminosyrer, er biologisk aktivt.
Blant de kjente bakterielle ST-peptidene er: E. co//'ST Ib (Moseley et al. 1983 Infect. Immun. 39:1167) som har den modne aminosyresekvensen Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:_); E. coli ST la (So og McCarthy 1980 Proe. Nati. Acad. Sei. USA 77:4011) som har den modne aminosyresekvensen Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr (SEKV ID NR:_); E. coli ST I<*>(Chan og Giannella 1981 J. Biol. Chem. 256:7744) som har den modne aminosyresekvensen Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Tyr Pro Ala Cys Ala Gly Cys Asn (SEKV ID NR: ); C. freundii ST-peptid (Guarino et al. 1989 Infect. Immun. 57:649) som har den modne aminosyresekvensen Asn Thr Phe Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Ala Gly Cys Tyr (SEKV ID NR: ); Y. enterocolitica ST-peptider, Y-ST(Y-STa), Y-STb og Y-STc (gjennomgått i Huang et al. (1997) Microb. Pathog. 22:89) som har de følgende pro-form aminosyresekvensene: Gin Ala Cys Asp Pro Pro Ser Pro Pro Ala Glu Val Ser Ser Asp Trp Asp Cys Cys Asp Val Cys Cys Asn Pro Ala Cys Ala Gly Cys (SEKV ID NR: ) (så vel som en Ser-7 til Leu-7-variant av Y-STa (SEKV ID NR: ), (Takao et al. 1985 Eur. J. Biochem. 152:199)); Lys Ala Cys Asp Thr Gin Thr Pro Ser Pro Ser Glu Glu Asn Asp Asp Trp Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Ala Gly Cys (SEKV ID NR:_); Gin Glu Thr Ala Ser Gly Gin Val Gly Asp Val Ser Ser Ser Thr Ile Ala Thr Glu Val Ser Glu Ala Glu Cys Gly Thr Gin Ser Ala Thr Thr Gin Gly Glu Asn Asp Trp Asp Trp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Phe Gly Cys (SEKV ID NR: ), henholdsvis; Y. kristensenii ST-peptid som har den modne aminosyresekvensen Ser Asp Trp Cys Cys Glu Val Cys Cys Asn Pro Ala Cys Ala Gly Cys (SEKV ID NR:_); V. cholerae non-01 ST-peptid (Takao et al. (1985) FEBS lett. 193:250) som har den modne aminosyresekvensen Ile Asp Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly Cys Leu Asn (SEKV ID NR: ); og V. mimicus ST-peptid (Arita (1991) et al. FEMS Microbiol. Lett. 79:105) som har den modne aminosyresekvensen Ile Asp Cys Cys Glu Ile Cys Cys Asn Pro Ala Cys Phe Gly Cys Leu Asn (SEKV ID NR: ). Tabellen nedenfor gir sekvenser av hele eller en del av flere modne ST-peptider. Slike peptider er anvendelige GCC-agonister. Den umodne (inkludert pre og pro-regioner) formen av E. coli ST-1A (ST-P)-protein har sekvensen: mkklmlaifisvlsfpsfsqstesldsskekitletkkcdwknnsekksenmnntfyccelccnpacagcy (SEKV ID NR:_); se GenBank<®>Aksesjonsnummer P01559 (gi:123711). Pre-sekvensen strekker seg fra aa 1-19. Pro-sekvensen strekker seg fra aa 20-54. Det modne proteinet strekker seg fra 55-72. Den umodne (inkludert pre og pro-regioner) formen av E. coli ST-1B (ST-H)-proteinet har sekvensen: mkksilfiflsvlsfspfaqdakpvesskekitleskkcniakksnksgpesmnssnyccelccnpactgcy (SEKV ID NR: ; se GenBank<®>Aksesjonsnummer P07965 (gi: 3915589)). Den umodne (inkludert pre og pro-regioner) formen av Y. enterocolitica ST-proteinet har sekvensen: mkkivfvlvlmlssfgafgqetvsgqfsdalstpitaevykqacdpplppaevssdwdccdvccnpacagc (SEKV ID NR:_; se GenBank<®>Aksesjonsnummer S25659 (gi: 282047)).
Peptidene heri har, i likhet med de bakterielle ST-peptidene, seks Cys-rester. Disse seks Cys-restene danner tre disulfidbindinger i den modne og aktive formen av peptidet. Dersom de seks Cys-restene er identifisert, fra den amino til den karboksyterminale enden av peptidet, som A, B, C, D, E og F, dannes disulfidbindingene som følger: A-D, B-E, og C-F. Dannelsen av disse bindingene er ansett for å være viktig for GC-C-reseptorbinding. Visse av peptidene heri omfatter et potensielt funksjonelt kløyvingssete for chymotrypsin, for eksempel, en Trp, Tyr eller Phe lokalisert mellom enten Cys B og Cys D eller mellom Cys E og Cys F. Kløyving ved hvilket som helst kløyvingssete for chymotrypsin reduserer eller fjerner peptidets evne til å binde til GC-C-reseptoren.
I menneskekroppen produseres en inaktiv form av chymotrypsin, chymotrypsinogen i pankreas. Når dette inaktive enzymet når tynntarmen omdannes det til aktivt chymotrypsin ved fjerning av to dipeptider. Aktivt chymotrypsin kan potensielt kløyve peptider ved peptidbindingen på den karboksyterminale siden av Trp, Tyr eller Phe. Tilstedeværelsen av aktivt chymotrypsin i fordøyelseskanalen kan potensielt føre til kløyving av visse av peptidene ifølge foreliggende oppfinnelse som har et passende plassert funksjonelt kløyvingssete for chymotrypsin. Det er forventet at kløyving med chymotrypsin vil moderere virkningen av et peptid ifølge foreliggende oppfinnelse som har et passende plassert chymotrypsin-kløyvingssete ettersom peptidet passerer gjennom fordøyelseskanalen.
Trypsinogen er, i likhet med chymotrypsin, en serinprotease som produseres i pankreas og er til stede i fordøyelseskanalen. Den aktive formen, trypsin, vil kløyve peptider som har en Lys eller Arg. Tilstedeværelsen av aktivt trypsin i fordøyelseskanalen kan føre til kløyving av visse av peptidene ifølge foreliggende oppfinnelse som har et passende plassert funksjonelt kløyvingssete for trypsin. Det er forventet at kløyving med chymotrypsin vil moderere virkningen av et peptid ifølge foreliggende oppfinnelse som har et passende plassert trypsin-kløyvingssete ettersom peptidet passerer gjennom fordøyelseskanalen.
Mange gastrointestinale forstyrrelser, inkludert IBS, er forbundet med abdominal eller visceral smerte. Visse peptider ifølge foreliggende oppfinnelse omfatter analgesiske eller antinociceptive tag's slik som den karboksyterminale sekvensen AspPhe umiddelbart etter en Trp, Tyr eller Phe som danner et funksjonelt kløyvingssete for chymotrypsin eller etter Lys eller Arg som danner et funksjonelt kløyvingssete for trypsin. Chymotrypsin i fordøyelseskanalen kan potensielt kløyve slike peptider umiddelbart karboksyterminalt for Trp, Phe eller Tyr-resten, hvilket frigir dipeptidet, AspPhe. Dette dipeptidet har blitt vist å ha analgesisk aktivitet i dyremodeller (Abdikkahi et al. 2001, Fundam Clin Pharmacol 15:117-23; Nikfaret al 1997, 29:583-6; Edmundson et al 1998, Clin Pharmacol Ther 63:580-93). På denne måten kan slike peptider behandle både smerte og inflammasjon. Andre analgesiske peptider kan være til stede ved den karboksyterminale enden av peptidet (for eksempel etter et funksjonelt kløyvingssete) inkludert: endomorfin-1, endomorfin-2, nocistatin, dalargin, lupron og substans P.
Flere av de anvendelige peptidene er basert på kjernesekvensen: Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr. For å danne en variant som har et potensielt funksjonelt kløyvingssete for chymotrypsin i stand til å inaktivere peptidet, kan enten Leu (understreket) eller Thr (understreket) erstattes med Trp, Phe eller Tyr eller både Leu og Thr kan ersattes med (uavhengig) Trp, Phe eller Tyr. For å danne en variant som har et analgesisk dipeptid, etterfølges kjernesekvensen av Asp Phe. Den karboksyterminale Tyr i kjernesekvensen kan tillate at dipeptidet Asp Phe frigis ved chymotrypsin i fordøyelseskanalen. Kjernesekvensen kan eventuelt innledes av Asn Ser Ser Asn Tyr eller Asn.
Anvendelige varianter basert på kjernesekvensen omfatter følgelig:
I noen tilfeller fremstilles peptidene ifølge foreliggende oppfinnelse som et prepro-protein som omfatter den aminoterminale ledersekvensen: mkksilfiflsvlsfspfaqdakpvesskekitleskkcniakksnksgpesmn. Når peptidet produseres av en bakteriecelle, for eksempel E. coli, vil den foregående ledersekvensen kløyves og det modne peptidet vil bli sekretert effektivt fra bakteriecellen. U.S. patent nr. 5,395,490 beskriver vektorer, ekspresjonssystemer og fremgangsmåter for effektiv fremstilling av ST-peptider i bakterieceller og fremgangsmåter for å oppnå effektiv sekresjon av modne ST-peptider. Vektorene, ekspresjonssystemene og fremgangsmåtene beskrevet i U.S. patent nr. 5,395,490 kan anvendes for å fremstille ST-peptidene og varianter av ST-peptidene heri.
Varianter av peptider
Varianter av peptider kan omfatte én, to, tre, fire, fem, seks, sju, åtte, ni eller ti (i noen utførelsesformer færre enn 5 eller færre enn 3 eller 2 eller færre) aminosyresubstitusjoner sammenlignet med SEKV ID NR: til . Substitusjonen(e) kan være konservative eller ikke-konservativ
e. De naturlig forekommende aminosyrene kan substitueres med D-isomerer av hvilken som helst aminosyre, ikke-naturlige aminosyrer og andre grupper. En konservativ aminosyresubstitusjon fører til endring av en aminosyre med en likt fungerende aminosyre, eller aminosyre med lik ladning, polaritet eller hydrofobisitet. Ved noen posisjoner kan til og med konservative aminosyresubstitusjoner redusere aktiviteten av peptidet. En konservativ substitusjon kan erstatte en naturlig forekommende aminosyre med en ikke-naturlig forekommende aminosyre. Aminosyresubstitusjonene blant naturlig forekommende aminosyrer er listet opp i Tabell il.
Under noen omstendigheter kan det være ønskelig å behandle pasienter med en variant av et peptid som binder til og aktiverer intestinal GC-C-reseptor, men er mindre aktiv enn ikke-variant formen av peptidet. Denne reduserte aktiviteten kan komme av redusert affinitet for reseptoren eller en redusert evne til å aktivere reseptoren når den først er bundet eller redusert stabilitet av peptidet.
Fremstilling av peptider
Nyttige peptider kan produseres enten i bakterier omfattende, uten begrensning, E. coli, eller i andre eksisterende systemer for peptid eller proteinproduksjon (for eksempel Bacillus subtilis, baculovirus-ekspresjonssystemer ved anvendelse av Drosophila Sf9-celler, gjær eller filamentøs sopp-ekspresjonssystemer, mammalsk celle-ekspresjonssystemer), eller de kan fremstilles kjemisk.
Dersom peptidet eller varianten av peptidet skal fremstilles i bakterier, for eksempel E. coli, vil nukleinsyremolekylet som koder for peptidet foretrukket også kode for en ledersekvens som tillater sekresjon av det modne peptidet fra cellen. Følgelig kan sekvensen som koder for peptidet omfatte pre-sekvensen og pro-sekvensen av, for eksempel, et naturlig forekommende bakterielt ST-peptid. Det sekreterte modne peptidet kan renses fra dyrkningsmediet.
Sekvensen som koder for et peptid ifølge foreliggende oppfinnelse inserteres foretrukket inn i en vektor i stand til å levere og opprettholde nukleinsyremolekylet i en bakteriecelle. DNA-molekylet kan inserteres inn i en autonomt replikerende vektor (egnede vektorer omfatter, for eksempel, pGEM3Z og pcDNA3, og derivater derav). Vektorens nukleinsyre kan være et bakterie- eller bakteriofag-DNA slik som bakteriofag lambda eller M13 og derivater derav. Konstruksjon av en vektor inneholdende en nukleinsyre beskrevet heri kan etterfølges av transformasjon av en vertscelle slik som en bakterie. Egnede bakterieverter omfatter men er ikke begrenset til, E. coli, B. subtilis, Pseudomonas, Salmonella. Den genetiske konstruksjonen omfatter også, i tillegg til det kodende nukleinsyremolekylet, elementer som muliggjør ekspresjon, slik som en promoter og reguleringssekvenser. Ekspresjonsvektorene kan inneholde transkripsjons kontrollsekvenser som styrer initiering av transkripsjon, slik som promoter, enhancer, operator og repressor-sekvenser. Mange forskjellige transkripsjonskontrollsekvenser er velkjente for fagfolk på området. Ekspresjonsvektoren kan også omfatte en reguleringssekvens for translasjon (for eksempel en utranslatert 5'-sekvens, en utranslatert 3-sekvens, eller et indre ribosombindingssete). Vektoren kan være i stand til autonom replikasjon eller den kan integrere inn i verts-DNA for å sikre stabilitet under peptidproduksjon.
Den proteinkodende sekvensen som omfatter et peptid ifølge foreliggende oppfinnelse kan også fusjoneres til en nukleinsyre som koder for en polypeptid affinitets-tag, for eksempel glutation S-transferase (GST), maltose E-bindende protein, protein A, FLAG-tag, heksa-histidin, myc-tag eller influensa HA-tag, for å lette rensing. Affinitets-tag'en eller markørfusjonen forbinder leserammen for peptidet av interesse til leserammen for genet som koder for affinitets-tag'en slik at det frembringes en translasjonen fusjon. Ekspresjon av fusjonsgenet fører til translasjon av et enkelt polypeptid som omfatter både peptidet av interesse og affinitets-tag'en. I noen tilfeller hvor affinitets-tag benyttes, vil DNA-sekvens som koder for et gjenkjenningssete for protease fusjoneres mellom leserammene for affinitets-tag'en og peptidet av interesse.
Genetiske konstruksjoner og fremgangsmåter egnet for fremstilling av umodne og modne former av peptidene og variantene ifølge foreliggende oppfinnelse i protein-ekspresjonssystemer andre enn bakterier, og velkjente for fagfolk på området, kan også anvendes for å fremstille peptider i et biologisk system.
Modne peptider og varianter derav kan syntetiseres ved fastfase-metoden ved anvendelse av en automatisert peptid-syntetiserer. Peptidet kan for eksempel syntetiseres på Cyc(4-CH2Bxl)-OCH2-4-(oksymetyl)-fenylacetamidometyl-resin ved anvendelse av et dobbelt koblings ("double coupling")-program. Beskyttelsesgrupper må anvendes passende for å danne det riktige disulfidbindingsmønsteret. For eksempel kan de følgende beskyttelsesgruppene anvendes: t-butyloksykarbonyl (alfa-aminogrupper); acetamidometyl (thiol-grupper av Cys-restene B og E); 4-metylbenyl (thiol-grupper av Cys-restene C og F); benzyl (y-karboksyl av glutaminsyre og hydroksylgruppen av treonin, dersom til stede); og brombenzyl (fenolgruppe av tyrosin, dersom til stede). Kobling bevirkes med symmetrisk anhydrid av t-butoksylkarbonylaminosyrer eller hydroksybenzotriazolester (for asparagin eller glutamin-rester), og beskyttelsesgrupper fjernes fra peptidet og det kløyves fra den faste bæreren i hydrogenfluorid, dimetylsulfid, anisol og p-tiokresol ved anvendelse av 8/1/1/0,5-ratio (volum/volum/volum/vekt) ved 0°C i 60 min. Etter fjerning av hydrogenfluorid og dimetylsulfid ved redusert trykk og anisol og p-tiokresol ved ekstraksjon med etyleter og etylacetat sekvensielt, ekstraheres uforedlede peptider med en blanding av 0,5M natriumfosfatbuffer, pH 8,0 og N,N-dimetylformamid ved anvendelse av en ratio på 1/1, volum/volum. Disulfidbindingen for Cys-restene B og E dannes ved anvendelse av dimetylsulfoksid (Tam et al.(1991) J. Am. Chem. Soc. 113:6657-62). Det resulterende peptidet renses deretter ved reversfase kromatografi. Disulfidbindingen mellom Cys-restene C og F dannes ved først å oppløse peptidet i 50% eddiksyre i vann. Mettet jodløsning i glasial eddiksyre tilsettes (1 ml jodløsning pr. 100 ml løsning). Etter inkubasjon ved romtemperatur i to dager i en lukket glassbeholder, fortynnes løsningen fem ganger med avionisert vann og ekstraheres med etyleter fire ganger for å fjerne ureagert jod. Etter fjerning av den gjenværende mengden av etyleter ved rotasjonsfordampning blir løsningen av uforedlet produkt lyofolisert og renset ved suksessiv reversfase kromatografi.
Peptider kan også syntetiseres ved mange andre metoder omfattende fastfasesyntese ved anvendelse av tradisjonell FMOC-beskyttelse (dvs., kobling med DCC-HOBt og regenerering med piperdin i DM F). Cys tiol-grupper kan trityl-beskyttes. Behandling med TFA kan anvendes for endelig regenerering av peptidet og frigjøring av peptidet fra fastfase-resinen. I mange tilfeller er luftoksidasjon tilstrekkelig til å oppnå korrekt dannelse av disulfidbinding.
Intestinal GC- C reseptor- bindingsanalyse
Evnen for peptider og andre agenser til å binde til den intestinale GC-C-reseptoren kan undersøkes som følger. Celler fra den T84 humane colon karcinom-cellelinjen (American Type Culture Collection (Bethesda, Md.)) dyrkes til konfluens i 24-brønners dyrkingsplater med en 1:1-blanding av Ham's F12-medium og Dulbecco's modified Eagle's medium (DMEM), supplert med 5% føtalt kalveserum. Celler anvendt i analysen er typisk mellom passasjene 54-60.1 korthet vaskes T84 celle-monolag i 24-brønners plater to ganger med 1 ml bindingsbuffer (DMEM inneholdende 0,05% bovint serumalbumin og 25 mM HEPES, pH 7,2), inkuberes deretter i 30 min ved 37°C i nærvær av modent radioaktivt merket E. coli ST-peptid og prøvematerialet ved forskjellige konsentrasjoner. Cellene blir deretter vasket fire ganger med 1 ml DMEM og solubilisert med 0,5 ml/brønn 1N NaOH. Nivået av radioaktivitet i det solubiliserte materialet bestemmes deretter ved anvendelse av standardmetoder.
Eksempel 1: Fremstilling av varianter av ST-peptider og villtype ST-peptid
1a: Fremstilling av rekombinante varianter av ST-peptider og villtype ST-peptid
En variant av ST-peptid med sekvensen: Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:5) ble fremstilt rekombinant og testet i en dyremodell. Et peptid som har sekvensen av villtype ST-peptid ble også fremstilt (SEKV ID NR:4).
Peptidene ifølge SEKV ID NR:5 og SEKV ID NR:4 ble fremstilt som prepro-proteiner ved anvendelse av vektorer fremstilt som følger. En sekvens som koder foren varmestabil enterotoksin pre-pro-sekvens ble amplifisert fra pGK51/pGSK51 (ATCC 67728) ved anvendelse av oligonukleotid M03514
NR:_)) og oligonukleotid M03515 (5'
CACACCTCGAGTTAGGTCTCCATGCTTTCAGGACCACTTTTATTAC 3' (SEKV
ID NR: )). Amplifiseringsproduktfragmentet ble kløyvet med Ndel/Xhol og ligert til T7-ekspresjonsvektoren, pET26b(+) (Novagen) kløyvet med Ndel/Xhol for å danne plasmid MB3976. Regionen som koder for pre-pro-proteinet ble sekvensert og funnet å kode for aminosyresekvensen: mkksilfiflsvlsfspfaqdakpagsskekitleskkcnivkksnksapesm (SEKV ID NR: ) som skiller seg fra aminosyresekvensen av varmestabilt enterotoksin a2 forløper (sta2; mkksilfiflsvlsfspfaqdakpagsskekitleskkcnivkknnesspesm (SEKV ID NR: ); GenBank® Aksesjonsnummer Q47185, Gl: 3913876) ved tre posisjoner (angitt ved understrekning og fet skrift) nær den C-terminale enden. For å danne ekspresjonsvektorer med pre-prosekvensen, ble komplemetære oligo som koder for hver ST-peptidvariant eller villtype ST-peptid hybridisert og klonet inn i ekspresjonsvektoren MB3976. For å danne MB3984 (som koder for (SEKV ID NR:4-peptid (villtype ST-peptid) som et prepro-protein), inneholdende aminosyresekvensen, NSSNYCCELCCNPACTGCY (SEKV ID NR:_) fusjonert nedstrøms for pre-prosekvensen, ble MB 3976 kløyvet med Bsal/Xhol og ligert til hybridiserte oligos M03621 (5' CAGTAATTGCTACTATTC3' (SEKV ID NR:_). For å danne MB3985 (som koder for SEKV ID NR:5 som et prepro-protein) inneholdende den følgende aminosyresekvensen, NSSNYCCEYCCNPACTGCY fusjonert nedstrøms for pre-prosekvensen, ble MB 3976 kløyvet med Bsal/Xhol og ligert til hybridiserte oligos
Peptidene ifølge SEKV ID NR:5 og SEKV ID NR:4 ble fremstilt som følger. Ekspresjonsvektorene ble transformert inn i E. co//-bakterievert BL21 A DE3 (Invitrogen). En enkelt koloni ble inokulert og dyrket med risting over natten ved 30°C i L medium + 25 mg/l kanamycin. Overnatt-kulturen ble tilsatt til 3,2 I batch-medium (Glukose 25 g/l, casminosyrer 5 g/l, gjærekstrakt 5 g/l, KH2PO413,3 g/l, (NH4)2HP02 4 g/l, MgS04-7H20 1,2 g/l, sitronsyre 1,7 g/l, EDTA 8,4 mg/l, C0CI2-6H20 2,5 mg/l, MnCI2-4H20 15 mg/l, CuCI2-4H20 1,5 mg/l, H3BO33 mg/l, Na2Mo04-2H20 2,5 mg/l, Zn-acetat-2H20 13 mg/l, jern(lll)-citrat 100 mg/l, kanamycin 25 mg/l, antiskum DF2041 ml/l) og fermentert ved anvendelse av de følgende prosessparametrene: pH 6,7 - kontroll med kun base (28% NH4OH), 30°C, lufting: 5 liter pr. minutt. Etter det initielle konsumet av batch-glukose (basert på overvåking av nivåer av oppløst oksygen (DO)), ble 1,5 I næringsmedium
(glukose 700 g/l, casaminosyrer 10 g/l, gjærekstrakt 10 g/l, MgSC>4-7H20 4 g/l, EDTA 13 mg/l, CoCI2-6H20 4 mg/l, MnCI2-4H20 23,5 mg/l, CuCI2-4H20 2,5 mg/l, H3BO3 5 mg/l, Na2Mo04-2H20 4 mg/l, Zn-acetat-2H20 16 mg/l, jern(lll)-citrat 40 mg/l, antiskum DF2041 ml/l) tilsatt ved en tilførselshastighet regulert for å opprettholde 20% DO. IPTG ble tilsatt til 0,2 mM 2 timer etter oppstart av tilførsel. Den totale gangtiden var omtrent 40-45 timer (til tømming av tilførsel).
Celler ble oppsamlet ved sentrifugering ved 5,000 g i 10 minutter. Cellepelleten ble kastet og supernatanten ble passert gjennom en 50 Kd ultrafiltreringsenhet. 50 Kd-filtratet (0,6 liter) ble fylt på en 110 ml Q-Sepharose fast Flow-kolonne (Amersham Pharmacia, ekvilibrert med 20 mMTris-HCI pH 7,5) ved en strømningshastighet på 400 ml/time. Kolonnen ble vasket med seks volumer 20 mM Tris-HCI pH 7,5 og proteiner ble eluert med 50 mM eddiksyre og fraksjoner på 50 ml ble oppsamlet. Fraksjoner inneholdende variant av ST-peptid eller villtype ST-peptid ble samlet og løsningsmidlet ble fjernet ved rotasjonsfordampning. De tørkede proteinene ble resuspendert i 10 ml 8% eddiksyre, 0,1% trifluoreddiksyre (TFA) og fylt på en Varian Polaris C18-A-kolonne (250 X 21,2 mm 10 um, ekvilibrert med samme buffer) ved en strømningshastighet på 20 ml/min. Kolonnen ble vasket med 100 ml 8% metanol, 0,1 % TFA og utviklet med en gradient (300 ml) på 24 til 48% metanol, 0,1% TFA, og fraksjoner på 5 ml ble oppsamlet. Fraksjoner inneholdende peptid ble samlet og løsningsmidlet ble fjernet ved rotasjonsfordampning. Peptidene ble oppløst i 0,1% TFA og lyofilisert.
SEKV ID NR:5- og SEKV ID NR:4-peptidfraksjonene ble analysert ved standard LCMS og HPLC. LCMS-analyse avslørte at SEKV ID NR:5-peptid er mer homogent enn SEKV ID NR:4-peptid (se Figur 1a; legg merke til at SEKV ID NR:5-peptid fremviser færre topper (Panel B) enn SEKV ID NR:4-peptid (Panel A)).
1b: Fremstilling av syntetiske varianter av ST-peptider og villtype ST-peptid
Peptider ble syntetisert kjemisk av et kommersielt peptidsyntese-firma. Det ble oppnådd forskjellige utbytter av peptider avhengig av effektiviteten av kjemisk syntese. Følgelig var de fire peptidene, i rekkefølge med hensyn til minskende utbytte: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:3), 10-20% utbytte; Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:6); Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:5); Asn Ser Ser Asn Tyr Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEKV ID NR:SEKV ID NR:4), <5% utbytte. Følgelig kan de spesifikke aminosyreendringene innført i peptidene danne forbedrede fremstillingsegenskaper.
Figur 1 b viser den totale ionekromatografprofilen for syntetisk fremstilt SEKV ID NR:3-peptid. Figur 1c viser den totale ionekromatografprofilen for den tomme kontrollprøven. Det er én stor topp til stede i SEKV ID NR:3-peptidprøven som ikke er til stede i kontrollprøven. Kvantitativ analyse antyder at SEKV ID NR:3-peptidet er >98% rent.
Eksempel 2: Aktivering av intestinal GC-C-reseptor ved en variant av ST-peptid og ST-peptid
Evnen til SEKV ID NR:5, SEKV ID NR:4 og SEKV ID NR:3 til å aktivere intestinal GC-C-reseptor ble vurdert i en analyse ved anvendelse av den humane colon karcinom-cellelinjen T84 (American Type Culture Collection (Bethesda, Md.). For analysen ble celler dyrket til konfluens i 24-brønners dyrkningsplater med en 1:1-blanding av Ham's F12-medium og Dulbecco's modified Eagle's medium (DMEM), supplert med 5% føtalt kalveserum og ble anvendt ved mellom passasjene 54 og 60.
I korthet ble monolag av T84-celler i 24-brønners plater vasket to ganger med 1 ml/brønn DMEM, og deretter inkubert ved 37°C i 10 min med 0,45 ml DMEM inneholdende 1 mM isobutylmetylxantin (IBMX), en syklisk nukleotid fosfodiesterase-inhibitor. Test-peptider (50 ul) ble deretter tilsatt og inkubert i 30 minutter ved 37°C. Mediene ble aspirert og reaksjonen ble deretter avsluttet ved tilsetning av iskald 0,5 ml 0,1 N HCI. Prøvene ble holdt på is i 20 minutter og deretter evaporert til tørrhet ved anvendelse av en varmepistol eller vakuumsentrifugering. De tørkede prøvene ble resuspendert i 0,5 ml fosfatbuffer tilveiebrakt i Cayman Chemical Cyclic GMP EIA-kit (Cayman Chemical, Ann Arbor, Ml). Syklisk GMP ble målt ved EIA i henhold til fremgangsmåter vist i Cayman Chemical Cyclic GMP EIA-kifet.
Figur 2 viser aktiviteten av kjemisk syntetiserte peptid-varianter i denne GC-reseptoraktivitetsanalysen. I denne analysen hadde SEKV ID NR:4 og to forskjellige SEKV ID NR:3-peptider (SEKV ID NR:3 (a) og SEKV ID NR:3 (b), syntetisert ved to forskjellige metoder) aktivitet komparabel med SEKV ID NR:4. SEKV ID NR:5 og SEKV ID NR:4-peptid ble syntetisert kjemisk på en måte identisk med den for SEKV ID NR:3 (b).
Eksempel 3: SEKV ID NR:5 og SEKV ID NR:4øker intestinal transitt hos mus
For å bestemme hvorvidt peptidene øker hastigheten av gastrointestinal transitt, ble peptidene og kontroller undersøkt ved anvendelse av en murin gastrointestinal transitt (GIT)-analyse (Moon et al. Infection and Immunity 25:127, 1979). I denne analysen administreres trekull, som lett kan visualiseres i magetarmkanalen til mus etter administrering av en prøve-forbindelse. Avstanden tilbakelagt av trekullet måles og uttrykkes som prosentandel av den totale lengden av colon.
Mus ble fastet med fri tilgang til vann i 12 til 16 timer før behandlingen med peptid eller kontrollbuffer. Peptidene ble administrert oralt ved 1 ug/kg - 1 mg/kg peptid i buffer (20 mM Tris pH 7,5) 7 minutter før det ble gitt en oral dose av 5% aktivert karbon (Aldrich 242276-250G). Til kontrollmus ble det kun administrert buffer før det ble gitt en dose aktivert karbon. Etter 15 minutter ble musene avlivet og deres tarmer fra magen til caecum ble dissekert. Den totale lengden av tarmen så vel som avstanden tilbakelagt fra magen til trekull-fronten ble målt for hvert dyr og resultatene er uttrykt som prosenten av den totale lengden av tarmen tilbakelagt av trekull-fronten. Alle resultatene er angitt som gjennomsnittet for 10 mus ± standardavvik. En sammenligning av avstanden tilbakelagt av trekullet mellom musene behandlet med peptid versus musene behandlet med vehikkel alene ble utført ved anvendelse av en Students t-test og en statistisk sigifikant forskjell ble tatt i betraktning for P<0,05. P-verdier er beregnet ved anvendelse av en tosidet T-Test forutsatt ulike varianser.
Som det kan ses i Figur 3a, b, øker villtype ST-peptid (SEKV ID NR:4, (Sigma-Aldrich, St Louis, MO); 0,1 mg/kg), syntetisk fremstilt SEKV ID NR:3 og Zelnorm<®>
(0,1 mg/kg), et medikament godkjent for IBS som er en agonist for serotonin-reseptoren 5HT4, den gastrointestinale hastigheten av transitt i denne modellen.
Figur 4a viser resultatet av en undersøkelse som viser at intestinal transitt-rate øker med en økende dose av enten rekombinant syntetisert SEKV ID NR:4 eller SEKV ID NR:5. Figur 4b viser resultatene av en undersøkelse som viser at både kjemisk syntetisert SEKV ID NR:4 og SEKV ID NR:3-peptid øker intestinale transitt-rater mer enn både Tris-buffer alene eller en ekvivalent dose Zelnorm<®>.
Et identisk eksperiment ble utført for å bestemme om SEKV ID NR:3 er effektiv i et behandlingsregime med kronisk dosering. I korthet doseres 8 uker gamle CD1 hunn-mus oralt én gang pr. dag i 5 dager med enten SEKV ID NR:3 (0,06 mg/kg eller 0,25 mg/kg i 20mM Tris pH 7,5) eller vehikkel alene (20mM Tris pH 7,5). På den femte dagen utføres en GIT-analyse identisk med den ovenfor med unntak av at 200 ul av en 10% trekull-løsning administreres. Figur 4c viser resultatene av en undersøkelse som viser at både kjemisk syntetisert SEKV ID NR:3 og Zelnorm<®>er effektive i en mus gastrointestinal motilitetsanalyse ved kronisk dosering (daglig i 5 dager). Resultatene er vist side om side med akutt dosering (1 dag).
Eksempel 4: SEKV ID NR:5-peptid og SEKV ID NR:4-peptid øker intestinal sekresjon hos nyfødte mus (SuMi assay)
SEKV ID NR:4-peptid og SEKV ID NR:5 ble undersøkt med hensyn til deres evne til å øke intestinal sekresjon ved anvendelse av en nyfødt mus-modell for intestinal sekresjon. I denne modellen administreres en test-forbindelse til nyfødte mus som er mellom 7 og 9 dager gamle. Etter at musene er avlivet, dissekeres magetarmkanalen fra magen til caecum ("tarmer"). Restene ("kadaveret") så vel som tarmer veies og ratioen av tarm- til kadaver-vekten beregnes. Dersom ratioen er over 0,09, kan det konkluderes med at test-forbindelsen øker intestinal sekresjon. Figur 5a viser en dose respons-kurve for villtype ST-peptid (SEKV ID NR:4) i denne modellen. Figur 5b viser dose respons-kurve for SEKV ID NR:3-peptidet i denne modellen. Disse data viser at villtype ST-peptid (ervervet fra TDT, Inc. West Chester, PA) og SEKV ID NR:3-peptidet øker intestinal sekresjon. Effekten av Zelnorm<®>ble også undersøkt. Som det kan ses fra Figur 5, øker ikke Zelnorm<®>ved 0,2 mg/kg intestinal sekresjon i denne modellen. Figur 6a viser en dose respons-kurve for det rekombinante SEKV ID NR:4-peptidet beskrevet ovenfor og det rekombinante SEKV ID NR:5-peptidet beskrevet ovenfor. Som det kan ses fra Figur 6a, øker begge peptider intestinal sekresjon i denne modellen. På lignenede måte viser figur 6b en dose respons-kurve for kjemisk syntetisert SEKV ID NR:5, SEKV ID NR:3 og SEKV ID NR:4 så vel som villtype ST-peptid (ervervet fra Sigma-Aldrich, St Louis, MO).
Dyremodeller for colonisk hvperalgesi
Hypersensitivitet for colorektal distensjon er vanlig hos pasienter med IBS og kan være ansvarlig for det viktigste symptomet på smerte. Både inflammatoriske og ikke-inflammatoriske dyremodeller for visceral hyperalgesi for distensjon har blitt utviklet for å undersøke effekten av forbindelser på visceral smerte ved IBS.
I. Trinitrobenzensulfonsvre ( TNBS)- indusert rektal allodvnia- modell
Hann Wistar-rotter (220-250 g) ble premedisinert med 0,5 mg/kg acepromazin injisert intraperitonealt (IP) og anestesert ved intramuskulær administrering av 100 mg/kg ketamin. Par av nikrom metalltråd elektroder (60 cm i lengde og 80 um i diameter) ble implantert i den tverrstripede muskel i abdomen, 2 cm lateralt fra den hvite linje. De frie endene av elektrodene ble eksternalisert på baksiden av nakken og beskyttet av en plasthylse festet til huden. Elektromyografiske (EMG) registreringer ble startet opp 5 dager etter kirurgi. Elektrisk aktivitet av abdominal tverrstripet muskel ble registrert med en elektroencefalograf-maskin (Mini VIII, Alvar, Paris, Frankrike) ved anvendelse av en short time konstant (0,03 sek.) for å fjerne lavfrekvente signaler (<3 Hz).
Ti dager etter kirurgisk implantasjon, ble trinitrobenzensulfonsyre (TNBS) administrert for å indusere rektal inflammasjon. TNBS (80 mg kg"<1>i 0,3 ml 50 % etanol) ble administrert intrarektalt gjennom et silikon gummi-kateter innført 3 cm fra anus under lett dietyleter-anestesi, som beskrevet (Morteau et al. 1994 Dig Dis Sei 39:1239). Etter administrering av TNBS ble rotter anbrakt i plast-tunneller hvor de ble strengt begrenset når det gjelder mobilitet i mange dager før kolorektal distensjon (CRD). Eksperimentell forbindelse ble administrert én time før CRD som ble utført ved å innføre inn i rektum, ved 1 cm fra anus, en 4 cm lang ballong konstruert fra et latex-kondom (Gue et al, 1997 Neurogastroenterol. Motil. 9: 271). Ballongen ble festet på et stivt kateter tatt fra en embolektomi-sonde (Fogarty). Ballongen festet til kateteret ble festet ved haleroten. Ballongen forbundet til en barostat, ble blåst opp progressivt ved trinn på 15 mmHg, fra 0 til 60 mmHg, hvor hvert trinn for oppblåsing varte i 5 min. Evaluering av rektal sensitivitet, som målt ved EMG, ble utført før (1-2 dager) og 3 dager etter rektal inngytelse av TNBS.
Antallet topp-utbrudd som korresponderer med abdominale kontraksjoner ble bestemt pr. 5 min perioder. Statistisk analyse av antallet av abdominale kontraksjoner og evaluering av dose-effekt-forhold ble utført ved en enveis variansanalyse (ANOVA) fulgt av en post-hoc (Student eller Dunnett test) og regresjonsanalyse for ED50 dersom hensiktsmessig.
Figur 7 viser resultatene av eksperiment i hvilket SEKV ID NR:3-aktivitet ble analysert i den TNBS colorektale modellen. Signifikante reduksjoner i abdominal respons er observert ved 0,3 ug/kg og 3 ug/kg SEKV ID NR:3. Disse resultatene viser at SEKV ID NR:3 reduserer smerte forbundet med colorektal distensjon i denne dyremodellen.
II. Stress- indusert hvperalgesi- modell
I hann Wistar-rotter (200-250 g) implanteres kirurgisk nikrom metalltråd elektroder som i TNBS-modellen. Ti dager etter kirurgisk implantasjon utføres partiell tvang ("partial restraint") stress (PRS) som beskrevet av Williams et al. i to timer (Williams et al. 1988 Gastroenterology 64:611). I korthet ble, under lett anestesi med etyleter, skuldrene, de øvre forlemmene og brystkassen innhyllet i en begrensende sele av papirtape for å begrense, men ikke forhindre kroppsbevegelser. Kontroller, simulert-stressede dyr, blir anestesert men blir ikke pakket inn. Tretti minutter før slutten av PRS-sesjonen, ble test-forbindelse eller vehikkel administrert til dyrene. Tretti minutter til én time etter fullførelse av PRS, ble CRD-distensjonsmetoden utført som beskrevet ovenfor for TNBS-modellen med barostat ved trykk på 15, 30, 45 og 60mm Hg. Statistisk analyse av antallet utbrudd bestemmes og analyseres som i TNBS-modellen ovenfor.
Fenylbenzoquinon- indusert vridningsmodell
Den PBQ-induserte vridningsmodellen kan anvendes for å vurdere smerte kontroll-aktivitet for peptidene og GC-C-reseptoragonister ifølge foreliggende oppfinnelse. Denne modellen er beskrevet av Siegmund et al. (1957 Proe. Soc. Exp. Bio. Med. 95:729-731). I korthet injiseres, én time etter oral dosering med en test-forbindelse, for eksempel, et peptid, morfin eller vehikkel, 0,02% fenylbenzoquinon (PBQ)-løsning (12,5 ml/kg) ved intraperitoneal rute inn i musen. Antallet tøyninger og vridninger registreres fra femte til tiende minutt etter injeksjon av PBQ, og kan også telles mellom det 35. og 40. minuttet og mellom det 60. og 65. minuttet for å gi en kinetisk bedømmelse. Resultatene er uttrykt som antall tøyninger og vridninger (middelverdi ± SEM) og prosentandelen av variasjon av den nociceptive terskelen beregnet fra middelverdien for den vehikkel-behandlede gruppen. Den statistiske signifikansen av enhver forskjell mellom de behandlede gruppene og kontrollgruppen bestemmes ved en Dunnetts test ved anvendelse av residual varians etter en enveis variansanalyse (P< 0,05) ved anvendelse av SigmaStat Software.
Figurene 8a og 8b viser effekten av forskjellige doser av SEKV ID NR:5 og SEKV ID NR:3 i PBQ vridnings-analysen. Indometacin, et NSAID (ikke-steroidalt anti-inflammatorisk medikament) med kjent effekt med hensyn til smertekontroll, ble anvendt som den positive kontrollen i analysen. Signifikante reduksjoner i vridninger ble observert for SEKV ID NR:5 (1 mg/kg dose) og SEKV ID NR:3 (2,5 mg/kg dose) sammenlignet med vehikkel-kontrollen. Tap av virkekraft ved den høyeste dosen som undersøkes har også blitt observert for mange andre forbindelser (slik som 5HT-3-antagonister) undersøkt i lignende analyser. Resultatene av denne undersøkelsen antyder at både SEKV ID NR:5 og SEKV ID NR:3 har antinociceptive effekter i denne modellen for visceral smerte sammenlignet med de intermediære dosene av indometacin.
Eksempel 5: SEKV ID NR:3 Kd-bestemmeise
For å bestemme affiniteten av SEKV ID NR:3 for GC-C-reseptorer funnet i intestinal mukosa hos rotte, ble det utført en konkurrerende bindingsanalyse ved anvendelse av tarmepitelceller fra rotte. Epitelceller fra tynntarmen fra rotter ble oppnådd som beskrevet av Kessler et al. ( J. Biol. Chem. 245: 5281-5288 (1970)). I korthet ble dyr avlivet og deres bukhule avdekket. Tynntarmen ble renset med 300 ml iskald saltoppløsning eller PBS. 10 cm av tynntarmen målt ved 10 cm fra pylorus ble fjernet og kuttet i segmenter på 1 tomme. Intestinal mukosa ble presset ut fra tarmen ved svakt trykk mellom et stykke parafilm og en P-1000 pipettespiss. Tarmepitelceller ble anbrakt i 2 ml PBS og pipettert opp og ned med en 5 ml pipette for å danne en suspensjon av celler. Proteinkonsentrasjon i suspensjonen ble målt ved anvendelse av Bradford-metoden ( Anal. Biochem. 72: 248-254
(1976)).
En konkurrerende bindingsanalyse ble utført basert på fremgangsmåten ifølge Giannella et al. ( Am. J Physiol. 245: G492-G498) mellom [<125>1]-merket SEKV ID NR:4 og SEKV ID NR:3. Analyseblandingen inneholdt: 0,5 ml DME med 20 mM HEPES-KOH pH 7,0, 0,9 mg av cellesuspensjonen listet opp ovenfor, 21,4 fmol [<125>I]-SEKV ID NR:4 (42,8 pM), og ulike konsentrasjoner av konkurrent SEKV ID NR:3 (0,01 til 1000 nM). Blandingen ble inkubert ved romtemperatur i 1 time, og reaksjonen ble stoppet ved å anbringe blandingen på GF/B glassfiber-filtere (Whatman). Filtrene ble vasket med 5 ml iskald PBS og radioaktivitet ble målt. Figur 9 viser at Kd for SEKV ID NR:3 i denne analysen er 4,5 nm. % B/Bo er prosentandelen av ratioen av radioaktivitet i hver prøve (B) sammenlignet med radioaktiviteten bibeholdt i en kontrollprøve uten noen kald konkurrent (Bo). Giannella et al. ( Am. J. Physio. 245: G492-G498) observerte at Kd for villtype ST-peptid i denne samme analysen var~13 nm.
Eksempel 6: Farmakokinetiske egenskaper for SEKV ID NR:3
For å undersøke farmakokinetikken for SEKV ID NR:3, ble absorberbarheten undersøkt i mus ved å administrere SEKV ID NR:3 intravanøst via injeksjon i halen eller gitt oralt til 8 uker gamle CD1-mus. Serum ble oppsamlet fra dyrene ved forskjellige tidspunkter og undersøkt for tilstedeværelse av SEKV ID NR:3 ved anvendelse av kompetitiv enzym-bundet immunoabsorbent assay (Oxoid, ST EIA kit, Cat#TD0700). Analysen benyttet monoklonale antistoffer mot ST-peptid (antistoffer gis i Oxoid-kifet) og syntetisk fremstilt SEKV ID NR:3. Figur 10a viser absorpsjonsdata for intravenøst og oralt administrert SEKV ID NR:3 som detektert ved ELISA-analysen. SEKV ID NR:3 synes å bli minimalt systemisk absorbert og er < 2,2% biotilgjengelig.
Et lignende biotilgjengelighetsstudie ble utført i hvilket det ble anvendt LCMS heller enn ELISA for å detektere SEKV ID NR:3. Initielt ble serumprøver ekstrahert fra helblod fra eksponerte mus og kontrollmus, deretter injisert direkte (10 ml) til en in-line fastfase-ekstraksjon (SPE)-kolonne (Waters Oasis HLB 25mm column, 2,0 x 15mm direkte forbundet) uten ytterligere bearbeidelse. Prøven på SPE-kolonnen ble vasket med en løsning av 5% metanol, 95% dH20 (2,1 ml/min, 1,0 minutt), derettert fylt i en analytisk kolonne ved anvendelse av en ventilbryter som plasserer SPE-kolonnen i en invertert strømingsbane på den analytiske kolonnen (Waters Xterra MS C8 5mm IS-kolonne, 2,1 x 20mm). Prøven ble eluert fra den analytiske kolonnen med en reversfase-gradient (Mobil fase A: 10 mM ammoniumhydroksid i dhbO, Mobil fase B: 10 mM ammoniumhydroksid i 80% acetonitril og 20% metanol; 20% B i de første 3 minuttene og deretter opptrapping til 95% B i løpet av 4 min. og holdt oppe i 2 min., alt ved en strømningshastighet på 0,4 ml/min.). Ved 9,1 minutter, går gradienten tilbake til de initielle betingelsene på 20% B i 1 min. SEKV ID NR:3 ble eluert fra den analytiske kolonnen ved 1,45 minutter, og ble detektert ved trippelkvadrupol massespektrometri (MRM, 764 (+2 charge state)> 182 (+1 charge state) Da; cone voltage = 30V; collision = 20 eV; parent resolution = 2 Da ved base peak; daughter resolution = 2 Da ved base peak). Instrumentrespons ble omregnet til konsentrasjonsenheter ved sammenligning med en standardkurve ved anvendelse av kjente mengder av kjemisk syntetisert SEKV ID NR:3 fremstilt og injisert i museserum ved anvendelse av samme fremgangsmåte.
Figur 10b viser absorpsjonsdata for IV og oralt administrert SEKV ID NR:3 som detektert ved LCMS. I denne analysen synes SEKV ID NR:3 på lignende måte minimalt systemisk absorbert og er < 0,11 % biotilgjengelig.
Administrering av peptider og GC- C- reseptoragonister
For behandling av gastrointestinale forstyrrelser, administreres peptidene og agonistene ifølge foreliggende oppfinnelse foretrukket oralt, for eksempel, som en
tablett eller en pulverkapsel inneholdende en forhåndsbestemt mengde av den aktive ingrediensen, pellett, gel, pasta, sukkerløsning, bolus, latverge, oppslemming, luktepose; kapsel; pulver; lyofilisert pulver; granuler; som en olje-i-vann-emulsjon eller en vann-i olje-emulsjon, via en liposomal formulering (se, for eksempel, EP 736299) eller i annen form. Oralt administrerte blandinger kan omfatte bindemidler, glattemidler og fuktighetsbevarer. Oralt administrerte formuleringer slik som tabletter kan eventuelt belegges eller markeres og kan formuleres slik at det tilveiebringes vedvarende, forsinket eller kontrollert frigjøring av den aktive bestanddelen deri. Peptidene og agonistene kan administreres sammen med andre agenser anvendt for å behandle gastrointestinale forstyrrelser inkludert men ikke begrenset til midlene beskrevet heri. Peptidene og agonistene kan også administreres ved rektalt suppositorium. For behandling av forstyrrelser utenfor magetarmkanalen slik som kongestiv hjertesvikt og benign prostata hypertrofi, administreres peptider og agonister foretrukket parenteralt eller oralt.
Peptidene beskrevet heri kan anvendes alene eller i kombinasjon med andre agenser. For eksempel kan peptidene administreres sammen med et analgesisk peptid eller forbindelse. Det analgesiske peptidet eller forbindelsen kan være kovalent bundet til et peptid beskrevet heri eller det kan være et atskilt agens som administreres sammen med eller sekvensielt med et peptid beskrevet heri i en kombinasjonsterapi.
Kombinasjonsterapi kan oppnås ved å administrere to eller flere agenser, for eksempel et peptid beskrevet heri og et analgesisk peptid eller forbindelse, som hver formuleres og administreres separat, eller ved å administrere to eller flere agenser i en enkelt formulering. Andre kombinasjoner er også omfattet ved kombinasjonsterapi. For eksempel kan to agenser formuleres sammen og administreres i forbindelse med en separat formulering inneholdende et tredje agens. Selv om de to eller flere agensene i kombinasjonsterapien kan administreres samtidig, er ikke dette nødvendig. For eksempel kan administrering av et første agens (eller kombinasjon av agenser) gå forut for administrering av et andre agens (eller kombinasjon av agenser) med minutter, timer, dager eller uker. Følgelig kan de to eller flere agensene administreres innen minutter i forhold til hverandre eller innen 1, 2, 3, 6, 9,12, 15, 18 eller 24 timer i forhold til hverandre eller innen 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12,14 dager i forhold til hverandre eller innen 2, 3, 4, 5, 6, 7, 8, 9 eller 10 uker i forhold til hverandre. I noen tilfeller er det til og med mulig med lengre intervaller. Selv om det i mange tilfeller er ønskelig at de to eller flere agensene som anvendes i en kombinasjonsterapi er til stede i pasientens kropp samtidig, er ikke dette nødvendig.
Kombinasjonsterapi kan også omfatte to eller flere administreringer av ett eller flere av agensene anvendt i kombinasjonen. Dersom, for eksempel, agens X og agens Y anvendes i en kombinasjon, kunne de administreres sekvensielt i hvilken som helst kombinasjon én eller flere ganger, for eksempel ifølge systemet X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, osv.
Agensene, alene eller i kombinasjon, kan kombineres med hvilken som helst farmasøytisk akseptabel bærer eller medium. Følgelig kan de kombineres med materialer som ikke produserer en ugunstig, allergisk eller på annen måte uønsket reaksjon ved administrering til en pasient. Bærerne eller mediene som anvendes kan omfatte løsningsmidler, dispergeringsmidler, belegg, absorpsjonsfremmende agenser, agenser for kontrollert frigivelse og én eller flere inerte tilsetningsmidler (som omfatter stivelser, polyoler, granuleringsmidler, mikrokrystallinsk cellulose, fortynningsmidler, glattemidler, bindemidler, disintegrasjonsmidler og lignende), osv. Om ønsket kan tablettdosene av de foreliggende sammensetningene belegges ved standard vandige eller ikke-vandige teknikker.
Sammensetninger ifølge foreliggende oppfinnelse kan også eventuelt omfatte andre terapeutiske bestanddeler, antiklumpingsmiddel, konserveringsmidler, søtningsmidler, fargestoffer, smakstoffer, tørkemidler, mykner, farger og lignende. Enhver slik eventuell bestanddel må være kompatibel med forbindelsen ifølge oppfinnelsen for å sikre stabiliteten av formuleringen.
Sammensetningen kan inneholde andre hjelpestoffer, omfattende for eksempel laktose, glukose, fruktose, galaktose, trehalose, sukrose, maltose, raffinose, maltitol, melezitose, stakyose, laktitol, palatinit, stivelse, xylitol, mannitol, myoinositol og lignende, og hydrater derav, og aminosyrer, for eksempel alanin, glysin og betain, og peptider og proteiner, for eksempel albumen.
Eksempler på tilsetningsmidler for anvendelse som de farmasøytisk akseptable bærerne og de farmasøytisk akseptable inerte bærerne og de tidligere nevnte ytterligere bestanddeler omfatter, men er ikke begrenset til bindemidler, fyllmidler, disintegrasjonsmidler, antimikrobielle midler og beleggningsmidler slik som: BINDEMIDLER: maisstivelse, potetstivelse, andre stivelser, gelatin, naturlige og syntetiske gummier slik som akasie, natriumalginat, alginsyre, andre alginater, pulverisert tragant, guargummi, cellulose og derivater derav (for eksempel etylcellulose, celluloseacetat, karboksymetylcellulosekalsium, natriumkarboksymetylcellulose), polyvinylpyrrolidon, metylcellulose, pregelatinisert stivelse (for eksempel STARCH1500® og STARCH 1500 LM®, solgt av Colorcon, Ltd.), hydroksypropylmetylcellulose, mikrokrystallinsk cellulose (for eksempel AVICEL™, slik som AVICEL-PH-101™, -103™ og -105™, solgt av FMC Corporation, Marcus Hook, PA, USA), eller blandinger derav,
FYLLMIDLER: talkum, kalsiumkarbonat (for eksempel granuler eller pulver), dibasisk kalsiumfosfat, tribasisk kalsiumfosfat, kalsiumsulfat (for eksempel granuler eller pulver), mikrokrystallinsk cellulose, pulverisert cellulose, dekstrater, kaolin, mannitol, kiselsyre, sorbitol, stivelse, pregelatinisert stivelse eller blandinger derav,
DISINTEGRASJONSMIDLER: agar-agar, alginsyre, kalsiumkarbonat, mikrokrystallinsk cellulose, krysskarmellose-natrium, crospovidon, polacrilin-kalium, natriumstivelsesglykolat, potet eller tapiokastivelse, andre stivelser, pregelatinisert stivelse, leire, andre alginer, andre celluloser, gummier eller blandinger derav,
GLATTEMIDLER: kalsiumstearat, magnesiumstearat, mineralolje, lett mineralolje, glyserin, sorbitol, mannitol, polyetylenglykol, andre glykoler, stearinsyre, natriumlaurylsulfat, talkum, hydrogenert vegetabilsk olje (for eksempel jordnøttolje, bomullsfrøolje, solsikkeolje, sesamolje, olivenolje, maisolje og soyaolje), sinkstearat, etyloleat, etyllaurat, agar, syloid silikagel (AEROSIL 200, W. R. Grace Co., Baltimore, MD USA), en koagulert aerosol av syntetisk silika (Deaussa Co., Piano, TX USA), en pyrogen silikondioksid (CAB-O-SIL, Cabot Co., Boston, MA USA), eller blandinger derav,
ANTIKLUMPINGSMIDLER: kalsiumsilikat, magnesiumsilikat, silikondioksid, colloidal silikondioksid, talkum eller blandinger derav,
ANTIMIKROBIELLE MIDLER: benzalkoniumklorid, benzetoniumklorid, benzosyre, benzylalkohol, butylparaben, cetylpyridiniumklorid, kresol, klorbutanol, dehydroeddiksyre, etylparaben, metylparaben, fenol, fenyletylalkohol, fenoksyetanol, fenylkvikksølvacetat, fenylkvikksølvnitrat, kaliumsorbat, propylparaben, natriumbenzoat, natriumdehydroacetat, natriumpropionat, sorbinsyre, thimersol, thymo, eller blandinger derav, og
BELEGNINGSMIDLER: natriumkarboksymetylcellulose, celluloseacetatftalat, etylcellulose, gelatin, farmasøytisk glasur, hydroksypropylcellulose, hydroksypropylmetylcellulose, hydroksypropylmetylcelluloseftalat, metylcellulose, polyetylenglykol, polyvinylacetatftalat, skjellakk, sukrose, titaniumdioksid, karnaubavoks, mikrokrystallinsk voks eller blandinger derav.
Midlene kan, enten i deres frie form eller som et salt, kombineres med en polymer slik som polymelke-glykolsyre (PLGA), poly-(l)-melke-glykol-tartarsyre (P(I)LGT)
(WO 01/12233), polyglykolsyre (U.S. 3,773,919), polymelkesyre (U.S. 4,767,628), poly(e-kaprolakton) og poly(alkylenoksid) (U.S. 20030068384) for å danne en formulering med vedvarende frigjøring. Slike formuleringer kan anvendes til implantater som frigjør et peptid eller et annet middel over en periode på noen få dager, noen få uker eller flere måneder avhengig av polymeren, partikkelstørrelsen av polymeren og størrelsen av implantatet (se, for eksempel, U.S. 6,620,422). Andre formuleringer med vedvarende frigjøring og polymerer for anvendelse er beskrevet i EP 0 467 389 A2, WO 93/24150, U.S. 5,612,052, WO 97/40085, WO 03/075887, WO 01/01964A2, U.S. 5,922,356, WO 94/155587, WO 02/074247A2, WO 98/25642, U.S. 5,968,895, U.S. 6,180,608, U.S. 20030171296, U.S. 20020176841, U.S. 5,672,659, U.S. 5,893,985, U.S. 5,134,122, U.S.
5,192,741, U.S. 5,192,741, U.S. 4,668,506, U.S. 4,713,244, U.S. 5,445,832 U.S. 4,931,279, U.S. 5,980,945, WO 02/058672, WO 9726015, WO 97/04744 og US20020019446. I slike formuleringer med vedvarende frigjøring blir mikropartikler av peptid kombinert med mikropartikler av polymer. En eller flere implantater med vedvarende frigjøring kan plasseres i tykktarmen, tynntarmen eller begge. U.S. 6,011,011 og WO 94/06452 beskriver en formulering med vedvarende frigjøring som tilveiebringer enten polyetylenglykoler (dvs. PEG 300 og PEG 400) eller triacetin. WO 03/053401 beskriver en formulering som både kan øke biotilgjengelighet og tilveiebringe kontrollert frigjøring av midlet i magetarm-kanalen. Ytterligere formuleringer med kontrollert frigjøring er beskrevet i WO 02/38129, EP 326 151, U.S. 5,236,704, WO 02/30398, WO 98/13029; U.S. 20030064105, U.S. 20030138488A1, U.S.20030216307A1, U.S. 6,667,060, WO 01/49249, WO 01/49311, WO 01/49249, WO 01/49311 og U.S. 5,877,224.
Agensene kan administreres, for eksempel, ved intravenøs injeksjon, intramuskulær injeksjon, subkutan injeksjon, intraperitoneal injeksjon, topisk, sublingval, intraartikulær (i leddene), intradermal, bukkal, oftalmisk (inkludert intraokulært), intranasalt (inkludert ved bruk av en kanyle), intraspinal, intratekal, eller ved andre ruter. Midlene kan administreres oralt, foreksempel som en tablett eller pulverkapsel inneholdende en forutbestemt mengde av den aktive ingrediensen, gel, pellett, pasta, sukkerløsning, bolus, latverge, oppslemming, kapsel, pulver; lyofilisert pulver, granuler, luktepose, som en løsning eller en suspensjon i en vandig eller ikke-vandig væske, som en flytende olje-i-vann-emulsjon, som en flytende vann-i olje-emulsjon, via en micellær formulering (se for eksempel WO 97/11682), via en liposomal formulering (se, for eksempel, EP 736299, WO 99/59550 og WO 97/13500) eller i annen form. Oralt administrerte blandinger kan omfatte bindemidler, glattemidler, inerte fortynningsmidler, overflateaktive eller dispergeringsmidler, smaksstoffer og fuktighetsbevarer. Oralt administrerte formuleringer slik som tabletter kan eventuelt belegges eller merkes og kan formuleres slik at det tilveiebringes vedvarende, forsinket eller kontrollert frigjøring av den aktive ingrediensen deri. Midlene kan også administreres transdermalt (dvs. via plaster av reservoar-type eller matriks-type, mikronåler, termal porering, hypoderme nåler, iontoforese, elektroporering, ultralyd eller andre former for sonoforese, jetinjeksjon, eller en kombinasjon av hvilke som helst av foregående metodene (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:115-124)). Midlene kan administreres ved anvendelse av høyhastighets transdermal partikkelinjeksjonsteknikk ved anvendelse av hydrogel partikkelformuleringen beskrevet i U.S. 20020061336. Ytterligere partikkelformuleringer er beskrevet i WO 00/45792, WO 00/53160 og WO 02/19989. Et eksempel på en transdermal formulering omfattende plaster og absorpsjonsfremmeren dimetylisosorbid kan finnes i WO 89/04179. WO 96/11705 tilveiebringer formuleringer egnet for transdermal administrering. Midlene kan administreres i form av et suppositorium eller ved andre metoder for vaginal eller rektal administrering. Midlene kan administreres i en transmembranformulering som beskrevet i WO 90/07923. Midlene kan administreres ikke-invasivt via de dehydrerte particiclene beskrevet i U.S. 6,485,706. Midlet kan administreres i en medikamentformulering med enterisk belegg som beskrevet i WO 02/49621. Midlene kan administreres intranasalt ved anvendelse av formuleringen beskrevet i U.S. 5,179,079. Formuleringer egnet for parenteral injeksjon er beskrevet i WO 00/62759. Midlene kan administreres ved anvendelse av caseinformuleringen beskrevet i U.S. 20030206939 og WO 00/06108. Midlene kan administreres ved anvendelse av de partikulære formuleringene beskrevet i U.S. 20020034536.
Midlene, alene eller i kombinasjon med andre egnede komponenter, kan administreres ved pulmonal rute ved anvendelse av flere teknikker omfattende men ikke begrenset til intratrakeal inndrypping (levering av løsning inn i lungene ved sprøyte), intratrakeal levering av liposomer, innblåsing (administrering av pulverformulering ved sprøyte eller hvilken som helst annen lignende anordning inn i lungene) og aerosolinhalasjon. Aerosoler (for eksempel jet eller ultrasoniske forstøvere, inhalatorer med oppmålt dose (MDI), og inhalatorer med tørt pulver (DPI)) kan også anvendes ved intranasale anvendelser. Aerosolformuleringer er stabile dispersjoner eller suspensjoner av fast materiale og flytende dråper i et gassformet medium og kan plasseres inn i trykkisolerte akseptable drivmidler, slik som hydrofluroalkaner (HFA, dvs. HFA-134a og HFA-227, eller en blanding derav), diklordifluormetan (eller andre klorfluokarbon-drivmidler slik som en blanding av drivmidlene 11, 12, og/eller 114), propan, nitrogen og lignende. Pulmonale formuleringer kan omfatte permeasjons-fremmere slik som fettsyrer, og sakkarider, chelateringsmidler, enzymhemmer (for eksempel proteasehemmere), adjuvanser (for eksempel glykocholat, surfaktin, span 85 og nafamostat), konserveringsmidler (for eksempel benzalkoniumklorid eller klorbutanol), og etanol (normalt opp til 5 vekt% men muligens opp til 20 vekt%). Etanol er vanligvis omfattet i aerosolblandinger ettersom det kan forbedre funksjonen av doseringsventilen og i noen tilfeller også forbedre stabiliteten av dispersjonen. Pulmonale formuleringer kan også omfatte surfaktanter som omfatter men er ikke begrenset til gallesyresalter og de beskrevet i U.S. 6,524,557 og referanser deri. Surfaktantene beskrevet i U.S. 6,524,557, for eksempel et C8-C16-fettsyresalt, et gallesyresalt, et fosfolipid, eller alkylsakkarid er fordelaktige ved at noen av dem også ifølge rapporter øker absorpsjon av peptidet i formuleringen. Også egnet med hensyn til oppfinnelsen er tørrpulverformuleringer omfattende en terapeutisk effektiv mengde av aktiv forbindelse blandet med en passende bærer og tilpasset for anvendelse i forbindelse med en tørrpulver-inhalator. Fremmere av absorpsjon som kan tilsettes til tørrpulverformuleringer ifølge foreliggende oppfinnelse omfatter de beskrevet i U.S. 6,632,456. WO 02/080884 beskriver nye metoder for overflatemodifikasjon av pulvere. Aerosolformuleringer kan omfatte U.S. 5,230,884, U.S. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437, U.S. 20030165436, og WO 96/40089 (som omfatter vegetabilsk olje). Formuleringer med vedvarende frigjøring egnet for inhalasjon er beskrevet i U.S. 20010036481A1, 20030232019A1 og U.S. 20040018243A1 så vel som i WO 01/13891, WO02/067902, WO 03/072080 og WO 03/079885. Pulmonale formuleringer inneholdende mikropartikler er beskrevet i WO 03/015750, U.S. 20030008013 og WO 00/00176. Pulmonale formuleringer omfattende pulver i stabil glasstilstand er beskrevet i U.S. 20020141945 og U.S. 6,309,671. Andre aerosolformuleringer er beskrevet i EP1338272A1 WO 90/09781, U.S. 5,348,730, U.S. 6,436,367, WO 91/04011 og U.S. 6,294,153 og U.S. 6,290,987 beskriver en liposombasert formulering som kan administreres via aerosol eller andre metoder. Pulverformuleringer for inhalasjon er beskrevet i U.S. 20030053960 og WO 01/60341. Midlene kan administreres intranasalt som beskrevet i U.S. 20010038824.
Løsninger av medikament i bufret saltoppløsning og lignende vehikler blir vanlig anvendt for fremstilling av en aerosol i et forstøvningsapparat. Enkle forstøvningsapparater virker ved Bernoulli's prinsipp og anvender en strøm av luft eller oksygen for å frembringe spraypartiklene. Mer komplekse forstøvningsapparater anvender ultralyd for å danne spraypartiklene. Begge typer er velkjente på området og er beskrevet i standard lærebøker innen farmasi slik som Sprowls' American Pharmacy og Remington's The Science and Practice of Pharmacy. Andre anordninger for frembringelse av aerosoler anvender komprimerte gasser, vanligvis hydrofluorkarbonder og klorfluorkarboner, som blandes med medikamentet og hvilke som helst nødvendige tilsetningsmidler i en trykkisolert beholder, disse anordningene er likeledes beskrevet i standard lærebøker slik som Sprowls og Remington.
Midlene kan være en fri syre eller base, eller et farmakologisk akseptabelt salt derav. Faste stoffer kan oppløses eller dispergeres umiddelbart før administrering eller tidligere. I noen tilfeller omfatter preparatene et konserveringsmiddel for å forebygge vekst av mikroorganismer. De farmasøytiske formene egnet for injeksjon kan omfatte sterile vandige eller organiske løsninger eller dispersjoner som omfatter, for eksempel vann, en alkohol, et organisk løsningsmiddel, en olje eller annet løsningsmiddel eller dispergeringsmiddel (for eksempel glyserol, propylenglykol, polyetylenglykol og vegetabilske oljer). Formuleringene kan inneholde antioksidanter, buffere, bakteriostatiske midler og oppløsninger som gjør formuleringen isoton med blodet til den tiltenkte resipienten, og vandige og ikke-vandige sterile suspensjoner som kan omfatte suspenderingsmidler, solubiliseringsmidler, tykningmidler, stabiliseringsmidler og konserveringsmidler. Farmasøytiske midler kan steriliseres ved filtersterilisering eller ved andre egnede metoder, midlet kan fusjoneres til immunglobuliner eller albumin, eller inkorporeres i et lipsom for å forbedre halveringstid. Midlet kan også konjugeres til polyetylenglykol (PEG)-kjeder. Metoder for pegylering og ytterligere formuleringer inneholdende PEG-konjugater (dvs. PEG-baserte hydrogeler, PEG-modifiserte liposomer) kan finnes i Harris og Chess, Nature Reviews Medikament Discovery 2: 214-221 og referansene deri. Peptider kan også modifiseres med alkylgrupper (for eksempel, C1-C20 rette eller forgrenede alkylgrupper); fettsyreradikaler; og kombinasjoner av PEG, alkylgrupper og fettsyreradikaler (se U.S. Patent 6,309,633; Soltero et al., 2001 Innovations in Pharmaceutical Technology 106-110). Midlet kan administreres via en nanokoklea ("nanocochleat") eller koklea leveringsvehikkel (BioDelivery Sciences International). Midlene kan leveres transmukosalt (dvs. over en mukosal overflate slik som vagina, øye eller nese) ved anvendelse av formuleringer slik som den beskrevet i U.S. 5,204,108. Midlene kan formuleres i mikrokapsler som beskrevet i WO 88/01165. Midlet kan administreres intra-oralt ved anvendelse av formuleringene beskrevet i U.S. 20020055496, WO 00/47203 og U.S. 6,495,120. Midlet kan leveres ved anvendelse av nanoemulsjonsformuleringer beskrevet i WO 01/91728A2.
Egnede farmasøytiske sammensetninger i overensstemmelse med oppfinnelsen vil generelt omfatte en mengde av de(n) aktive forbindelsen(e) sammen med et akseptabelt farmasøytisk fortynningsmiddel eller tilsettingsmiddel, slik som en steril vandig løsning, for å gi et spekter av endelige konsentrasjoner, avhengig av den tiltenkte anvendelsen. Teknikkene for fremstilling er generelt velkjente på området, som eksemplisiert ved Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Company, 1995).
Agensene beskrevet heri og agenser for kombinasjonsterapi kan pakkes som et kit som omfatter enkelt- eller multiple doser av ett eller flere agenser, som hvert er pakket eller formulert individuelt i kombinasjon. Følgelig kan ett eller flere agenser være til stede i en første beholder, og kifet kan eventuelt omfatte ett eller flere agenser i en andre beholder. Beholderen eller beholderne plasseres inne i en pakke, og pakken kan eventuelt omfatte instruksjoner for administrering eller dosering. Et kit kan omfatte ytterligere komponenter slik som sprøyter eller andre midler for å administrere agensene så vel som fortynningsmidler eller andre midler for formulering.
Metoder for å øke kjemisk og/eller fysisk stabilitet av midlene beskrevet heri finnes i U.S. 6,541,606, U.S. 6,068,850, U.S. 6,124,261, U.S. 5,904,935 og WO 00/15224, U.S. 20030069182 (via tilsetning av nikotinamid), U.S. 20030175230A1, U.S. 20030175230A1, U.S. 20030175239A1, U.S. 20020045582, U.S. 20010031726, WO 02/26248, WO 03/014304, WO 98/00152A1, WO 98/00157A1, WO 90/12029, WO 00/04880 og WO 91/04743, WO 97/04796 og referansene omtalt deri.
Metoder for å øke biotilgjengelighet av midlene beskrevet heri finnes i U.S. 6,008,187, U.S. 5,424,289, U.S. 20030198619, WO 90/01329, WO 01/49268, WO 00/32172 og WO02/064166. Glycyrrhizinat kan også anvendes som en fremmer for absorpsjon (se, for eksempel EP397447). WO 03/004062 gjør rede for Ulex europaeus I (UEA1) og UEAI-etterligninger som kan anvendes for å målrette midlene ifølge oppfinnelsen til magetarm-kanalen.
Midlene beskrevet heri kan fusjoneres til en modifisert versjon av blodserumproteinet transferrin. U.S. 20030221201, U.S. 20040023334, U.S. 20030226155, WO 04/020454 og WO04/019872 angir fremstilling og anvendelse av fusjonsproteiner med transferrin. Transferrin-fusjonsproteiner kan forbedre sirkulatorisk halveringstid og effektivitet, redusere uønskede bivirkninger og tillate redusert dosering.
Peptidene og agonistene ifølge oppfinnelsen kan uttrykkes rekombinant i bakterier. Bakterier som uttrykker peptidet eller agonistene kan administreres oralt, rektalt, mukosalt eller ved en annen administreringsmetode omfattende men ikke begrenset til de beskrevet heri.
Analgesiske midler i kombinasjonsterapi
Peptidene beskrevet heri kan anvendes i kombinasjonsterapi med et analgesisk middel, for eksempel en analgesisk forbindelse eller et analgesisk peptid. Disse peptidene og forbindelsene kan administreres med peptidene ifølge oppfinnelsen (samtidig eller sekvensielt). De kan også eventuelt være kovalent bundet eller knyttet til et peptid beskrevet heri for å danne terapeutiske konjugater. Blant anvendelige analgesiske midler er: Ca-kanal-blokkere, 5HT-reseptorantagonister (for eksempel 5HT3, 5HT4 og 5HT1-reseptorantagonister), opioid-reseptoragonister (loperamid, fedotozine og fentanyl), NK1-reseptorantagonister, CCK-reseptoragonister (for eksempel loksiglumid), NK1-reseptorantagonister, NK3-reseptorantagonister, norepinefrin-serotonin gjenopptak-inhibitorer (NSRI), vanilloid- og cannabanoid-reseptoragonister og sialorphin. Analgesiske midler innen de forskjellige klassene er beskrevet i litteraturen.
Blant de anvendelige analgesiske peptidene er sialorphin-relaterte peptider, inkludert de som omfatter aminosyresekvensen QHNPR (SEKV ID NR:), inkludert: VQHNPR (SEKV ID NR: )VRQHNPR (SEKV ID NR:); VRGQHNPR
(SEKV ID NR:); VRGPQHNPR (SEKV ID NR:) VRGPRQHNPR (SEKV ID NR:);
VRGPRRQHNPR (SEKV ID NR:); og RQHNPR (SEKV ID NR:). Sialorphin-relaterte peptider bindes til neprilysin og hemmer neprilysin-mediert nedbrytning av substans P og Met-enkefalin. Følgelig er forbindelser eller peptider som er inhibitorer for neprilysin anvendelige analgesiske agenser som kan administreres med peptidene ifølge foreliggende oppfinnelse i en tilleggsbehandling ("co-therapy") eller bundet til peptidene ifølge foreliggende oppfinnelse, for eksempel ved en kovalent binding. Sialophin og relaterte peptider er beskrevet i U.S. patent 6,589,750; U.S. 20030078200 A1; og WO 02/051435 A2.
Opioid-reseptorantagonister og agonister kan administreres med peptidene ifølge foreliggende oppfinnelse som tilleggsbehandling eller bundet til peptidet ifølge foreliggende oppfinnelse, for eksempel ved en kovalent binding. For eksempel er opioid-reseptorantagonister slik som nalokson, naltrexon, metylnalozone, nalmefen, cypridime, beta funaltrexamin, naloksonazine, naltrindol og nor-binaltorfimine antatt å være anvendelige ved behandling av IBS. Det kan være nyttig å formulere opioide antagonister av denne typen som en formulering med forsinket og vedvarende frigivelse slik at initiell frigivelse av antagonisten er mellom den distale tynntarmen og /eller ascendens colon. Slike antagonister er beskrevet i WO 01/32180 A2. Enkefalin pentapeptid (HOE825; Tyr-D-Lys-Gly-Phe-L-homoserin) er en agonist for mu og delta opioid-reseptorer og er antatt å være nyttig for å øke intestinal motilitet ( Eur. J. Pharm. 219:445,1992), og dette peptidet kan anvendes i konjunksjon med peptidene ifølge foreliggende oppfinnelse. Også anvendelig er trimebutin som er antatt å binde til mu/delta/kappa opioid-reseptorer og aktivere frigivelse av motilin og modulere frigivelse av gastrin, vasoaktivt intestinalt peptid, gastrin og glukagoner. Kappa opioid-reseptoragonister slik som fedotozine, asimadoline og ketocyclazocine og forbindelser beskrevet i WO 03/097051 A2 kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse. I tillegg kan mu-opioid-reseptoragonister slik som morfin, difenyloksylat, frakefamide (H-Tyr-D-Ala-Phe
(F)-Phe-NH2; WO 01/019849 A1) og loperamid anvendes.
Tyr-Arg (kyotorfin) er et dipeptid som virker ved å stimulere frigivelsen av met-enkefaliner for å frembringe en analgesisk effekt ( J. Biol. Chem 262:8165,1987). Kyotorfin kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
Kromogranin-avledet peptid (CgA 47-66; se for eksempel Ghia et al. 2004 Regulatory Peptides 119:199) kan anvendes med eller bundet til peptidene ifølge oppfinnelsen.
CCK-reseptoragonister slik som caerulein fra amfibier og andre arter er anvendelige analgetiske midler som kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
Conotoksin-peptider representerer en stor klasse av analgesiske peptider som fungerer ved spenningsvoktede Ca-kanaler, NMDA-reseptorer eller nikotinreseptorer. Disse peptidene kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
Peptidanaloger av thymulin (FR søknad 2830451) kan ha analgesisk virkning og kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
CCK (CCKa eller CCKb)-reseptorantagonister, inkludert loxiglumid og dexloxiglumid (R-isomeren av loxiglumid) (WO 88/05774) kan ha analgesisk aktivitet og kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
Andre anvendelige analgesiske midler omfatter 5-HT4-agonister slik som tegaserod (Zelnorm®), mosapride, metoklopramid, zacopride, cisaprid, renzapride, benzimidazolon-derivater slik som BIMU 1 og BIMU 8 og lirexaprid. Slike agonister er beskrevet i: EP1321142A1, WO 03/053432A1, EP 505322A1, EP 505322B1, US 5,510,353, EP 507672A1, EP 507672 B1 og US 5,273,983. Kalsium-kanal-blokkere slik som ziconotid og relaterte forbindelser beskrevet i, for eksempel, EP625162B1, US 5,364,842, US 5,587,454, US 5,824,645, US 5,859,186, US 5,994,305, US 6,087,091, US 6,136,786, WO 93/13128 A1, EP 1336409 A1, EP 835126 A1, EP 835126 B1, US 5,795,864, US 5,891,849, US 6,054,429, WO 97/01351 A1, kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
Forskjellige antagonister for NK-1, NK-2 og NK-3-reseptorene (for en gjennomgang se Giardina et al.2003 Drugs 6:758) kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
NK1-reseptorantagonister slik som: aprepitant (Merck & Co Inc), vofopitant, ezlopitant (Pfizer, Inc.), R-673 (Hoffmann-La Roche Ltd), SR-48968 (Sanofi Synthelabo), CP-122,721 (Pfizer.lnc), GW679769 (Glaxo Smith Kline), TAK-637(Takeda/Abbot), SR-14033 og relaterte forbindelser beskrevet i, for eksempel, EP 873753 A1, US 20010006972 A1, US 20030109417 A1, WO01/52844 A1,kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
NK-2 reseptorantagonister slik som nepadutant (Menarini Ricerche SpA), saredutant (Sanofi- Synthelabo), GW597599 (Glaxo Smith Kline), SR-144190 (Sanofi-Synthelabo) og UK- 290795 (Pfizer Inc) kan anvendes med eller bundet til peptidene ifølge oppfinnelsen.
NK3-reseptorantagonister slik som osanetant (SR-142801; Sanofi-Synthelabo), SSR-241586, talnetant og relaterte forbindelser beskrevet i, for eksempel, WO 02/094187 A2, EP 876347A1, WO 97/21680A1, US 6,277,862, WO 98/11090, WO 95/28418, WO 97/19927 og Boden et al. (J Med Chem. 39:1664-75, 1996) kan anvendes med eller bundet til peptidene ifølge oppfinnelsen.
Norepinefrin-serotonin gjenopptak-inhibitorer (NSRI) slik som milnacipran og relaterte forbindelser beskrevet i WO 03/077897 A1 kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse. Vanilloid-reseptorantagonister slik som arvanil og relaterte forbindelser beskrevet i WO 01/64212 A1 kan anvendes med eller bundet til peptidene ifølge foreliggende oppfinnelse.
De analgesiske peptidene og forbindelsene kan administreres med peptidene og agonister ifølge oppfinnelsen (samtidig eller sekvensielt). De analgesiske midlene kan også være kovalent bundet til peptidene og agonistene ifølge oppfinnelsen for å danne terapeutiske konjugater. Når analgetikumet er et peptid og er kovalent bundet til et middel beskrevet heri kan det resulterende peptidet også omfatte minst ett kløyvingssete for trypsin. Når det er til stede inne i peptidet, kan det analgesiske peptidet innledes med (dersom det er ved den karboksyterminale enden) eller etterfølges av (hvis det er ved den aminoterminale enden) et kløyvingssete for trypsin som tillater frigivelse av det analgesiske peptidet.
I tillegg til sialorphin-relaterte peptider, omfatter analgesiske peptider: AspPhe, endomorfin-1, endomorfin-2, nocistatin, dalargin, lupron, zicnotide og substans P.
Andre midler for anvendelse i kombinasjonsterapi
Også innenfor oppfinnelsen er farmasøytiske sammensetninger omfattende et peptid eller agonister ifølge oppfinnelsen og evt. et andre terapeutisk middel. Det andre terapeutiske midlet kan administreres for å behandle hvilken som helst tilstand for hvilken den er anvendelig, inkludert tilstander som ikke er ansett å være den primære indikasjonen for behandling med det andre terapeutiske midlet. Det andre terapeutiske midlet kan administreres samtidig eller sekvensielt. Det andre terapeutiske midlet kan være kovalent bundet til peptidene og agonister ifølge oppfinnelsen for å danne et terapeutisk konjugat. Når det andre terapeutiske midlet er et annet peptid, kan en linker inkludert de beskrevet heri anvendes mellom peptidet ifølge oppfinnelsen og det andre terapeutiske peptidet.
Eksempler på ytterligere terapeutiske midler for behandling av gastrointestinale og andre forstyrrelser omfatter: (1) Midler for behandling av konstipasjon (for eksempel en aktivator for kloridkanaler slik som den bisykliske fettsyren, Lubiproston (tidligere kjent som SPI-0211; Sucampo Pharmaceuticals, Inc.; Bethesda, MD), etavførende middel slik som MiraLax; Braintree Laboratories, Braintree MA); (2) syrereduserende midler slik som protonpumpehemmere (for eksempel omeprazol (Prilosec®, esomeprazol (Nexium®, lansoprazol (Prevacid®), pantoprazol (Protonix® og rabeprazol (Aciphex®)) og Histamin H2-reseptorantagonist (også kjent som H2 reseptorblokker inkludert cimetidin, ranitidin, famotidin og nizatidin); (3) prokinetiske midler omfattende metoklopramid (Reglan®, domperidon (Motilium®), erytromycin eller cisaprid (propulsid®) (4) pro-motilitet midler slik som det vasostatin-avledede peptidet, kromogranin A (4-16) (se, foreksempel, Ghia et al. 2004 Regulatory Peptides 121:31) eller motilinagonister (for eksempel GM-611 eller mitemcinalfumarat); (5) fullstendig eller partiell 5HT (for eksempel 5HT1, 5HT2, 5HT3, 5HT4) reseptoragonister eller antagonister (inkludert 5HT4 reseptoragonister (slik som tegaserod (ZELNORM®), mosaprid, metoklopramid, zacopride, cisaprid, renzapride, benzimidazolon-derivater slik som BIMU 1 og BIMU 8, og lirexapride. Slike agonister er beskrevet i: EP1321142 A1, WO03/053432A1, EP 505322A1, EP 505322B1, US 5,510,353, EP 507672A1, EP 507672 B1og US 5,273,983); 5HT3-reseptoragonister slik som MKC-733; og 5HT3-reseptorantagonister slik som alosetron og ATI-7000 (Aryx Therapeutics, Santa Clara CA); (6) muskarinreseptor-agonister; (7) anti-inflammatoriske midler; (8) krampestillende midler; (9) antidepressiva; (10) sentralt virkende analgesiske midler slik som opoidreseptor-agonister, opoidreseptor-antagonister (for eksempel naltrekson); (11) midler for behandling av Inflammatorisk tarmsykdom; (12) midler for behandling av Crohns sykdom og/eller colitis ulcerosa (for eksempel alequel (Enzo Biochem, Inc.; Farmingsale, NY), det anti-inflammatoriske peptidet RDP58 (Genzyme, Inc.; Cambridge, MA), og TRAFICET-EN™ (ChemoCentryx, Inc.; San Carlos, CA); (13) midler for behandling av gastrointestinal eller visceral smerte; (14) PDE (fosfodiesterase)-hemmere omfattende men ikke begrenset til de angitt heri; (15) avføringsmidler som trekker væske til tarmen (for eksempel VISICOL<®>, en kombinasjon av natriumfosfat monobasisk monohydrat og natriumfosfat dibasisk an hyd rat); (16) Kortikotropin-frigjørende faktor (CRF) reseptor-antagonister (inkludert NBI-34041 (Neurocrine Biosciences, San Diego, CA), CRH9-41, astressin, R121919 (Janssen Pharmaceutica), CP154,526, NBI-27914, Antalarmin, DMP696 (Bristol-Myers Squibb) CP-316,311 (Pfizer,Inc.), GW876008 (Neurocrine/Glaxo Smith Kline), ONO-2333Ms (Ono Pharmaceuticals), TS-041 (Janssen), AAG561 (Novartis) og de angitt i US 5,063,245, US 5,861,398, US 20040224964, US20040198726, US20040176400, US20040171607, US20040110815 og US20040006066); (17) glukagonlignende peptider (glp-1) og analoger derav (inkludert exendin-4) og hemmere av DPP-IV (DPP-IV medierer inaktivering av glp-1); (18) tofisopam, enantiomer ren R-tofisopam, og farmasøytisk akseptable salter derav (US 20040229867) (19) det trisykliske anti-depressive midlet av dibenzotiazepin-typen, tianeptin (Stablon (g)) og andre midler beskrevet i U.S. 6,683,072; (20) (E)-4(1,3bis (sykloheksylmetyl)-1,2,34,-tetrahydro-2,6-diono-9H-purin-8-yl)kanelsyre-nonaetylenglykolmetyleterester og relaterte forbindelser beskrevet i WO 02/067942; og (21) probiotikum PROBACTRIX<®>(The BioBalance Corporation; New York, NY) som inneholder mikroorganismer anvendelige for behandling av gastrointestinale forstyrrelser.
Peptidene og agonistene ifølge oppfinnelsen kan anvendes i kombinasjonsterapi med insulin og relaterte forbindelser omfattende primat, gnager eller kanin-insulin inkludert biologisk aktive varianter derav omfattende alleliske varianter, mer foretrukket human insulin tilgjengelig i rekombinant form. Kilder for human insulin omfatter farmasøytisk akseptable og sterile formuleringer slik som de tilgjengelige fra Eli Lilly (Indianapolis, Ind. 46285) som Humulin. TM. (human insulin rDNA-opprinnelse). Se THE PHYSICIAN'S DESK REFERENCE, 55. sup. th Ed. (2001) Medical Economics, Thomson Healthcare (angir andre egnede humane insuliner). Peptidene ifølge oppfinnelsen kan også anvendes i kombinasjonsterapi med midler som kan booste insulineffekter eller nivåer hos et subjekt ved
administrering, for eksempel glipizid og/eller rosiglitazon. Peptidene og agonistene ifølge oppfinnelsen kan anvendes i kombinasjonsterapi med SYMLIN®
(pramlintidacetat) og Exenatide® (syntetisk exendin-4; et peptid på 39 aminosyrer).
Peptidene og agonistene ifølge oppfinnelsen kan også anvendes i kombinasjonsterapi med agenser (for eksempel, Entereg(<TM>) (alvimopan; tidligere kalt adolor/ ADL 8-2698), conivaptan og relaterte agenser beskrivet i US 6,645,959) for behandling av postoperativ ileus.
Peptidene og agonistene ifølge oppfinnelsen kan anvendes i kombinasjonsterapi med et antihypertensivt middel inkludert men ikke begrenset til: (1) diuretika, slik som tiazider, omfattende klortalidon, klortiazid, diklorfenamid, hydroflumetiazid, indapamid, polytiazid, og hydroklortiazid; loop-diuretika, slik som bumetanid, etakrynsyre, furosemid, og torsemid; kalium sparing midler, slik som amilorid, og triamteren; og aldosteron-antagonister, slik som spironolakton, epirenon og lignende; (2) beta-adrenerge blokkere slik som acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, karteolol, karvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, og timolol, og lignende; (3) kalsiumkanal blokkere slik som amlodipin, aranidipin, azelnidipin, barnidipin, benidipin, bepridil, cinaldipin, clevidipine, diltiazem, efonidipin, felodipin, gallopamil, isradipin, lacidipin, lemildipin, lercanidipin, nikardipin, nifedipin, nilvadipin, nimodepin, nisoldipin, nitrendipin, manidipin, pranidipin og verapamil, og lignende; (4) angiotensinomdannende enzym (ACE)-hemmere slik som benazepril;
kaptopril; ceranapril; cilazapril; delapril; enalapril; enalopril; fosinopril; imidapril; lisinopril; losinopril; moexipril; quinapril; quinaprilat; ramipril; perindopril; perindropril; quanipril; spirapril; tenocapril; trandolapril, og zofenopril, og lignende; (5) nøytrale endopeptidase-hemmere slik som omapatrilat, cadoxatril og ecadotril, fosidotril, sampatrilat, AVE7688, ER4030, og lignende; (6) endotelinantagonister slik som tezosentan, A308165 og YM62899, og lignende; (7) vasodilatorer slik som hydralazin, klonidin, minoxidil, og nikotinylalkohol, og lignende; (8) angiotensin II reseptor-antagonister slik som aprosartan, kandesartan, eprosartan, irbesartan, losartan, olmesartan, pratosartan, tasosartan, telmisartan, valsartan, og EXP-3137, FI6828K, og RNH6270, og lignende; (9) a//3-adrenerge blokkere slik som nipradilol, arotinolol og amosulalol, og lignende; (10) alfa 1-blokkere, slik som terazosin, urapidil, prazosin, tamsulosin, bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHP 164 og XEN010, og lignende; (11) alfa 2-agonister slik som lofexidin, tiamenidin, moxonidin, rilmenidin og guanobenz og lignende;
(12) aldosteron-hemmere, og lignende; og
(13) angiopoietin-2-bindende midler slik som de angitt i WO 03/030833.
Peptidene og agonistene ifølge oppfinnelsen kan også anvendes i kombinasjonsterapi med ett eller flere av de følgende agensene anvendelige ved behandling av respiratoriske og andre forstyrrelser: (1) /3-agonister omfattende men ikke begrenset til: albuterol (PROVENTIL®, SALBUTAMOI®, VENTOLIN®), bambuterol, bitoterol, klenbuterol, fenoterol, formoterol, isoetarin (BRONKOSOL®, BRONKOMETER®), metaproterenol (ALUPENT®, METAPREL®), pirbuterol (MAXAIR®), reproterol, rimiterol, salmeterol, terbutalin (BRETHAIRE®, BRETHINE®, BRICANYL®), adrenalin, isoproterenol (ISUPREL®), epinefrinbitartrat (PRIMATENE®), efedrin, orciprenlin, fenoterol og isoetarin; (2) steroider, omfattende men ikke begrenset til beklometason, beklometasondipropionat, betametason, budesonid, bunedosid, butixocort, dexametason, flunisolid, fluokortin, flutikason, hydrokortison, metylprednison, mometason, predonisolon, predonison, tipredan, tixocortal, triamcinolon, og triamcinolonacetonid; (3) /32-agonist-kortikosteroid-kombinasjoner [for eksempel, salmeterol-flutikason (ADVAIR®), formoterol-budesonid (SYMBICORT®)]; (4) leukotrien D4 reseptor-antagonister/leukotrien-antagonister/LTD4-antagonister (dvs., hvilken som helst forbindelse som er i stand til å blokkere, hemme, redusere eller på annen måte avbryte interaksjonen mellom leukotriener og Cys LTI-reseptoren) omfattende men ikke begrenset til: zafirlukast, montelukast, montelukast-natrium (SINGULAIR®), pranlukast, iralukast, pobilukast, SKB-106, 203 og forbindelser beskrevet å ha LTD4-antagoniserende aktivitet beskrevet i U.S. Patent Nr. 5,565,473; (5) 5-lipoksygenase-hemmere og/eller leukotrien biosyntese-hemmere [for eksempel zileutonand BAY1005 (CA registry 128253-31-6) ]; (6) histamin H1 reseptor-antagonister/antihistaminer (dvs. hvilken som helst forbindelse som er i stand til å blokkere, hemme, redusere eller på annen måte avbryte interaksjonen mellom histamin og dens reseptor) inkludert men ikke begrenset til: astemizol, akrivastin, antazolin, azatadin, azelastin, astamizol, bromfeniramin, bromfeniraminmaleat, carbinoxamin, carebastin, cetirizin, klorfeniramin, klorfeniraminmaleat, cimetidin, klemastin, cyclizine, cyproheptadin, deskarboetoksyloratadin, dexklorfeniramin, dimetinden, difenhydramin, difenylpyralin, doksylaminsuccinat, doxylarnin, ebastin, efletirizin, epinastin, farnotidin, fexofenadin, hydroksyzin, hydroksyzin, ketotifen, levokabastin, levocetirizin, levocetirizin, loratadin, meclizin, mepyramin, mequitazin, methdilazin, mianserin, mizolastin, noberastin, norasternizol, noraztemizole, fenindamin, pheniramine, picumast, prometazin, pynlamin, pyrilamin, ranitidin, temelastin, terfenadin, trimeprazin, tripelenamin og triprolidin; (7) et anticholinerg middel omfattende men ikke begrenset til: atropin, benztropin, biperiden, flutropium, hyoscyamin, ilutropium, ipratropium, ipratropiumbromid, metscopolamin, oksybutinin, rispenzepin, skopolamin og tiotropium; (8) et hostedempende middel omfattende men ikke begrenset til: dekstrometorfan, kodein og hydromorfon; (9) en dekongestant omfattende men ikke begrenset til: pseudoefedrin og fenylpropanolamin; (10) et slimløsende middel omfattende men ikke begrenset til: guafenesin, guaicolsulfat, terpin, ammoniumklorid, glyserol guaicolat, og iodinert glyserol; (11) en bronkodilator omfattende men ikke begrenset til: teofyllin og aminofyllin; (12) et anti-inflammatorisk middel omfattende men ikke begrenset til: fluribiprofen, diklofenak, indometacin, ketoprofen, S-ketroprofen, tenoksikam; (13) en PDE (fosfodiesterase)-hemmer omfattende men ikke begrenset til de som er angitt heri; (14) et rekombinant humanisert monoklonalt antistoff [for eksempel xolair (også kalt omalizumab), rhuMab og talizumab]; (15) en humanisert lunge surfaktant omfattende rekombinante former av surfaktant-proteinene SP-B, SP-C eller SP-D [for eksempel SURFAXIN®, tidligere kjent som dsc-104 (Discovery Laboratories)], (16) agenser som hemmer epitel natriumkanaler (ENaC) slik som amilorid og relaterte forbindelser; (17) antimikrobielle midler anvendt for å behandle pulmonale infeksjoner slik som acyklovir, amikacin, amoksicillin, doksycyklin, trimetoprin-sulfametoksazol, amfotericin B, azitromycin, klaritromycin, roksitromycin, klaritromycin, cephalosporiner (ceffoxitin, cefinetazol osv), ciprofloksacin, etambutol, gentimycin, ganciklovir, imipenem, isoniazid, itraconazol, penicillin, ribavirin, rifampin, rifabutin, amantadin, rimantidin, streptomycin, tobramycin og vancomycin; (18) midler som aktiverer kloridsekresjon gjennom Ca++-avhengige kloridkanaler (slik som purinerg reseptor (P2Y(2)-agonister); (19) midler som reduserer viskositet i sputum, slik som human rekombinant DNase 1, (Pulmozyme®); (20) ikke-steroidale anti-inflammatoriske midler (acemetacin, acetaminofen, acetylsalicylsyre, alklofenak, alminoprofen, apazon, aspirin, benoxaprofen, bezpiperylon, bucloxic syre, carprofen, clidanak, diklofenak, diklofenak, diflunisal, diflusinal, etodolak, fenbufen, fenbufen, fenklofenak, fenclozic syre, fenoprofen, fentiazac, feprazone, flufenaminsyre, flufenisal, flufenisal, fluprofen, flurbiprofen, flurbiprofen, furofenak, ibufenak, ibuprofen, indometacin, indometacin, indoprofen, isoxepak, isoxikam, ketoprofen, ketoprofen, ketorolak, meklofenaminsyre, meklofenaminsyr, mefenaminsyre, mefenaminsyre, miroprofen, mofebutazon, nabumeton-oksaprozin, naproksen, naproksen, nifluminsyre, oksaprozin, okspinak, oksyfenbutazon, fenacetin, fenylbutazon, fenylbutazon, piroksikam, piroksikam, pirprofen, pranoprofen, sudoksikam, tenoksikan, sulfasalazin, sulindak, sulindak, suprofen, tiaprofensyre, tiopinak, tioksaprofen, tolfenaminsyre, tolmetin, tolmetin, zidometacin, zomepirak, og zomepirak); og
(21) aerosoliserte antioksidant terapeutika slik som S-Nitrosoglutation.
Peptidene og agonistene ifølge oppfinnelsen kan anvendes i kombinasjonsterapi med et anti-fedmemiddel omfattende men ikke begrenset til: (1) 1ip HSD-1 (11-beta-hydroksysteroid dehydrogenase type 1)-hemmere, slik som BVT3498, BVT 2733,3-(1-adamantyl)-4-etyl-5-(etyltio)-4H-1,2,4-triazol, 3-(1-adamantyl)-5-(3,4,5-trimetoksyfenyl)-4-metyl-4H-1,2,4-triazol, 3-adamantanyl-4,5,6,7,8,9,10,11,12, 3a-dekahydro-1,2,4-triazolo [4,3-a][11] annulen, og forbindelsene angitt i WO 01/90091, WO 01/90090, WO 01/90092 og WO 02/072084; (2) 5HT (serotonin) transportør-hemmere, slik som paroksetin, fluoksetin (Prozac®), fenfluramin, fluvoksamin, sertralin og imipramin og de angitt i WO 03/00663; (3) 5HT-antagonister slik som de i WO 03/037871, WO 03/037887 og lignende; (4) 5HT1 a-modulatorer slik som de angitt i WO 03/031439 og lignende; (5) 5HT-2 agonister; (6) SHT2c (serotoninreseptor 2c)-agonister, slik som BVT933, DPCA37215, IK264, PNU 22394, WAY161503, R-1065, SB 243213 (Glaxo Smith Kline) og YM 348 og de angitt i U.S. Patent Nr. 3,914,250 og PCT-publikasjoner nr. WO02/36596, WO02/48124, WO02/10169, WO01/66548, WO02/44152, WO02/51844, WO02/40456 og WO02/40457; (7) 5HT6 reseptor-modulatorer, slik som de i WO03/030901, WO03/035061, WO03/039547 og lignende; (8) ACC2 (acetyl-CoA karboksylase-2)-hemmere; (9) acyl-østrogener, slik som oleoyl-estron, angitt i del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001) og Japansk patentsøknad nr. JP 2000256190; (10) alfa-lipoic syre (alfa-LA); (11) anoreksi bisykliske forbindelser slik som 1426 (ventis) og 1954 (Aventis), og forbindelsene angitt i WO00/18749, WO01/32638, WO01/62746, WO01/62747 og WO03/015769; (12) AOD9604; (13) apetittdempende midler slik som de ifølge WO03/40107; (14) ATL-962 (Alizyme PLC); (15) benzokain; (16) benzfetaminhydroklorid (Didrex); (17) blæretang (focus vesiculosus); (18) BRS3 (bombesinreseptor subtype 3)-agonister; (19) bupropion; (20) koffein; (21) CB 1 (kannabinoid-l-reseptor)-antagonist/ invers agonister, slik som rimonabant (Acomplia; Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY 65-2520 (Bayer), og SLV 319 (Solvay), og de angitt i US Patenter nr. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,532,237, 5,624,941, 6,028,084 og 6,509,367 og W096/33159, WO97/29079, W098/31227, W098/33765, WO98/37061, W098/41519, W098/43635, W098/43636, WO99/02499, WO00/10967, WO00/10968, WO01/09120, WO01/58869, WO01/64632, WO01/64633, W001/64634, WO01/70700, WO01/96330, WO02/076949, WO03/006007, WO03/007887, WO03/020217, WO03/026647, WO03/026648, WO03/027069, WO03/027076, WO03/027114, WO03/037332, WO03/040107, WO03/086940, WO03/084943 og US 6,509,367 og EPO-søknad nr. EP-658546; (22) CCK-agonister; (23) CCK-A (cholecystokinin-A)-agonister, slik som AR-R 15849, GI181771, JMV-180, A-71378, A-71623 og SR146131, og de beskrevet i U.S. Pat. Nr. 5,739,106; (24) chitosan; (25) kromium; (26) CNTF (Ciliær neurotrofiske faktorer), slik som GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), butabindid, PD170,292 og PD 149164 (Pfizer); (27) CNTF-derivater, slik som axokin (Regeneron), og de angitt i PCT-søknadene nr. WO 94/09134, WO 98/22128 og W099/43813; (28) konjugert linolensyre; (29) kortikotropinfrigjørende hormon-agonister; (30) dehydroepiandrosteron; (31) DGAT1 (diacylglyserol-acyltransferase 1)-hemmere; (32) DGAT2 (diacylglyserol-acyltransferase 2)-hemmere; (33) dikarboksylattransporter-hemmere; (34) dietylpropionhydroklorid (Tenuate); (35) dipeptidyl peptidase IV (DP-IV)-hemmere, slik som isoleucin-tiazolidid, valin-pyrrolidid, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP0177, SDZ 274-444 og forbindelsene angitt i PCT-publikasjoner nr. WO02/083128, WO02/062764, WO03/000180, WO03/000181, WO03/000250, WO03/002530, WO03/002531, WO03/002553, WO03/002593, WO03/004498, WO03/004496, WO03/017936, WO03/024942, WO03/024965, WO03/033524, WO03/037327 og EP1258476; (36) efedra;
(37) exendin-4 (en inhibitor for glp-1)
(38) FAS (fettsyre syntase)-hemmere, slik som Cerulenin og C75; (39) fettresorpsjon-hemmere slik som de ifølge WO03/053451, og lignende; (40) fettsyretransportør-hemmere; (41) fiber (psyllium, plantago, guarfiber); (42) galanin-antagonister; (43) galega (geitvikke); (44) garcinia cambogia; (45) germander (teucrium chamaedrys); (46) ghrelin-antagonister, slik som de angitt i PCT søknader nr. WO 01/87335, og WO 02/08250; (47) GLP-1 (glukagon-lignende peptid 1 )-agonister (for eksempel exendin-4); (48) glp-1 (glukagon-lignende peptid-1); (49) glukokortikoid-antagonister; (50) glukosetransportør-hemmere; (51) Veksthormon-secretagogue reseptoragonister/ antagonister, slik som NN703, heksarelin, MK-0677, SM-130686, CP-424,391, L-692,429 og L-163,255, og slik som de angitt i U.S. Pat. Nr. 6,358,951, U.S. Patentsøknader nr. 2002/049196 og 2002/022637, og PCT søknader nr. WO01/56592 og WO02/32888; (52) Veksthormon-secretagogue, slik som de angitt og spesifikt beskrevet i U.S. Pat. Nr. 5,536,716; (53) H3 (histamin H3)-antagonist/inverse agonister, slik som tioperamid, 3-(1 H-imidazol-4-yl)propyl N-(4-pentenyl)karbamat), klobenpropit, jodofenpropit, imoproxifan, GT2394 (Gliatech), og A331440, og de angitt i PCT-publikasjon nr.
WO02/15905 og 0-[3-(1H-imidazol-4-yl)propanol]karbamater (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidin-inneholdende histamin H3-reseptor-antagonister (Lazewska, D. et al., Pharmazie, 56:927-32 (2001), benzofenon-derivater og relaterte forbindelser (Sasse, A. et al., Arch.Pharm.
(Weinheim) 334:45-52 (2001)), substituerte N-fenylkarbamater (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)), og proxifan-derivater (Sasse, A. et al., J. Med. Chem.. 43:3335-43 (2000)) og histamin H3-reseptormodulatorer slik som de angitt i WO03/024928 og WO03/024929;
(54) interleukin-6 (IL-6) og modulatorer derav, som i WO03/057237 og lignende; (55) L-karnitin; (56) leptinderivater, slik som de angitt i U.S. Patenter nr. 5,552,524, 5,552,523, 5,552,522, 5,521,283, og PCT internasjonale publikasjoner nr. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, og WO 96/23520; (57) leptin, omfattende rekombinant human leptin (PEG-OB, Hoffman La Roche) og rekombinant metionyl human leptin (Amgen); (58) lipase-hemmere, slik som tetrahydrolipstatin (orlistat/Xenical®), Triton WR1339, RHC80267, lipstatin, teasaponin og dietylumbelliferylfosfat, FL-386, WAY-121898, Bay-N-3176, valilacton, esteracin, ebelacton A, ebelacton B og RHC 80267, og de angitt i PCT publikasjon nr. WO01/77094 og U.S. Patenter nr. 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644, 4,189,438 og 4,242,453; (59) lipidmetabolisme-modulatorer slik som maslinic syre, erytrodiol, ursolin ("ursolic")-syre uvaol, betulinsyre, betulin og lignende og forbindelser angitt i WO03/011267; (60) Mc3r (melanokortin 3-reseptor)-agonister; (61) Mc4r (melanokortin 4-reseptor)-agonister, slik som CHIR86036 (Chiron), ME-10142, ME-10145 og HS-131 (Melacure), og de angitt i PCT-publikasjoner nr. WO99/64002, WO00/74679, WO01/991752, WO01/25192, WO01/52880, WO01/74844, WO01/70708, WO01/70337, WO01/91752, WO02/059095, WO02/059107, WO02/059108, WO02/059117, WO02/06276, WO02/12166, WO02/11715, WO02/12178, WO02/15909, WO02/38544, WO02/068387, WO02/068388, WO02/067869, WO02/081430, WO03/06604, WO03/007949, WO03/009847, WO03/009850, WO03/013509 og WO03/031410; (62) Mc5r (melanokortin 5-reseptor)-modulatorer, slik som de angitt i W097/19952, WO00/15826, WO00/15790, US 20030092041; (63) MCH2R (melanin-konsentrerende hormon 2R)-agonist/antagonister; (64) melanin-konsentrerende hormon-antagonister; (65) melanin-konsentrerende hormon 1-reseptor (MCHR)-antagonister, slik som T-226296 (Takeda), SNP-7941 (Synaptic) og de angitt i WO01/21169, WO01/82925, WO01/87834, WO02/051809, WO02/06245, WO02/076929, WO02/076947, WO02/04433, WO02/51809, WO02/083134, WO02/094799, WO03/004027, WO03/13574, WO03/15769, WO03/028641, WO03/035624, WO03/033476, WO03/033480 og Japanske patentsøknader nr. JP 13226269 og JP1437059; (66) melanokortin-agonister, slik som Melanotan II eller de beskrevet i WO 99/64002 og WO 00/74679; (67) Metformin (GLUCOPHAGE®); (68) mGluR5-modulatorer slik som de angitt i WO03/029210, WO03/047581, W003/048137, WO03/051315, WO03/051833, WO03/053922, WO03/059904 og lignende; (69) monoamin gjenopptak-inhibitorer, slik som sibutratmin (Meridia®/Reductil®) og salter derav, og forbindelsene angitt i U.S. Patenter nr. 4,746,680, 4,806,570 og 5,436,272, og U.S. Patent publikasjon nr. 2002/0006964, og WO01/27068, og WO01/62341; (70) NE (noradrenalin)-transporthemmere, slik som GW 320659, despiramin, talsupram og nomifensin; (71) nomame herba; (72) ikke-selektive serotonin/noradrenalin transporthemmere, slik som sibutramin eller fenfluramin; (73) NPY 1-antagonister, slik som BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A og de angitt i U.S. Pat. Nr. 6,001,836, og PCT-patenter publikasjoner nr. WO 96/14307, WO01/23387, WO 99/51600, WO 01/85690, WO01/85098, WO01/85173 og WO01/89528; (74) NPY5 (neuropeptid YY5)-antagonister, slik som 152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR235208, FR226928, FR240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, LY-366377, PD-160170, SR-120562A, SR-120819A, JCF-104 og H409/22 og forbindelsene angitt i U.S. Patenter nr. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,326,375, 6,329,395, 6,335,345, 6,337,332, 6,329,395 og 6,340,683, Europeiske patenter nr. EP-01010691 og EP-01044970 og PCT-publikasjoner nr. W097/19682, WO97/20820, WO97/20821, WO97/20822, WO97/20823, W098/27063, WO00/107409, WO00/185714, WO00/185730, WO00/64880, WO00/68197, WO00/69849, WO01/09120, WO01/14376, WO01/85714, WO01/85730, WO01/07409, WO01/02379, WO01/23388, WO01/23389, WO01/44201, WO01/62737, WO01/62738, WO01/09120, WO02/20488, WO02/22592, WO02/48152, WO02/49648, WO02/051806, WO02/094789, WO03/009845, WO03/014083, WO03/022849, WO03/028726 og Norman et le., L. Med. Chem. 43:4288-4312(2000); (75) opoid-antagonister, slik som nalmefen (REVEX®), 3-metoksynaltrekson, nalokson og naltrekson og de som er angitt i WO00/21509; (76) oreksin-antagonister, slik som SB-334867-A og de som er angitt i PCT-publikasjoner nr. WO01/96302, WO01/68609, WO02/44172, WO02/51232, WO02/51838, WO02/089800, WO02/090355, WO03/023561, WO03/032991 og WO03/037847; (77) PDE (fosfodiesterase)-hemmere omfattende men ikke begrenset til de som er angitt heri; (78) Peptid YY og fragmenter og varianter derav (for eksempel YY3-36 (PYY3-36) (N Eng. J. Med. 349:941, 2003; IKPEAPGE DASPEELNRY YASLRHYLNL VTRQRY (SEKV ID NR:XXX) og PYY-agonister slik som de som er angitt i WO03/026591; (79) fendimetrazin; (80) fentermin; (81) fosfattransportør-hemmere; (82) fosfodiesterase-3B (PDE3B)-hemmere; (83) fytofarm forbindelse 57 (CP 644,673); (84) pyruvat; (85) SCD-1 (stearoyl-CoA desaturase-1)-hemmere; (86) serotonin gjenopptak-hemmere, slik som deksfenfluramin, fluoksetin og de ifølge U.S. patent nr. 6,365,633 og WO01/27060 og WO01/162341; (87) T71 (tularik; Inc.; Boulder CO); (88) tyroidhormon P-agonister, slik som KB-2611 (KaroBioBMS), og de som er angitt i WO02/15845 og Japansk patentsøknad nr. JP 2000256190; (89) Topiramat (TOPIMAX®); (90) modulatorer for transkripsjonsfaktor slik som de angitt i WO03/026576; (91) UCP-1 (uncoupling protein-1), 2, eller 3-aktivatorer, slik som fytansyre, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5, 8,8-tetrametyl-2-nafalenyl)-1-propeny-l]benzosyre (TTNPB), retinoinsyre, og de som er angitt i PCT Patentsøknad nr. WO 99/00123; (92) /3-3 (beta-adrenerg reseptor 3)-agonister, slik som AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecadrine, Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly) og SR 59119A, og de som er angitt i US Patenter nr. 5,705,515, US 5,451,677 og PCT-publikasjoner nr. W094/18161, W095/29159, W097/46556, WO98/04526 og W098/32753, WO01/74782, WO02/32897, WO03/014113, WO03/016276, WO03/016307, WO03/024948, WO03/024953 og WO03/037881;
(93) /3-hydroksy-steroid dehydrogenase-1 -hemmere (/3-HSD-1) og
(94) /3-hydroksy-metylbutyrat.
Peptider og agonister kan anvendes for behandling av fedme og kan administreres som en koterapi sammen med elektrostimulering (US20040015201).
Peptidene og agonistene ifølge oppfinnelsen kan anvendes i kombinasjonsterapi med midler som aktiverer løselig guanylat cyklase, for eksempel de som er beskrevet i US20040192680.
Peptidene og agonistene ifølge oppfinnelsen kan anvendes i kombinasjonsterapi med en fosfodiesteraseinhibitor. PDE-hemmere innenfor formålet ifølge foreliggende oppfinnelse er de forbindelsene som saktner degraderingen av syklisk AMP (cAMP) og/eller syklisk GMP (cGMP) ved hemming av fosfodiesterasene, hvilket kan føre til en relativ økning av den intracellulære konsentrasjonen av cAMP og cGMP. Mulige PDE-hemmere innenfor formålet ifølge foreliggende oppfinnelse er primært de substansene som skal regnes opp av klassen bestående av PDE3-hemmere, klassen bestående av PDE4-hemmere og/eller klassen bestående av PDE5-hemmerne, spesielt de substansene som kan betegnes som blandede typer av PDE3/4-hemmere eller som blandede typer av PDE3/4/5-hemmere. Som et eksempel er de PDE-hemmerne som kan nevnes slike som er beskrevet og/eller fremlagt i de følgende patentsøknadene og patentene: : DE1470341, DE2108438; DE2123328, DE2305339, DE230S575, DE2315801, DE2402908, DE2413935, DE2451417, DE2459090, DE2646469, DE2727481, DE2825048, DE2837161, DE2845220, DE2847621, DE2934747, DE3021792, DE3038166, DE3044568, EP000718, EP0008408, EP0010759, EP0059948, EP0075436, EP0096517, EP0112987, EP0116948, EP0150937, EP0158380, EP0161632, EP0161918, EP0167121, EP0199127, EP0220044, EP0247725, EP0258191, EP027291O, EP0272914, EP0294647, EP0300726, EP0335386, EP0357788, EP0389282, EP0406958, EP0426180, EP0428302, EP0435811, EP0470805, EP0482208, EP0490823, EP0506194, EP0511865, EP0527117, EP0626939, EP0664289, EP0671389, EP0685474, EP0685475, EP0685479, JP92234389, JP94329652, JP95010875, U.S. Pat nr. 4,963,561,5,141,931, W09117991, WO9200968, W09212961, WO9307146, W09315044, W09315045, WO9318024, WO9319068, WO9319720, W09319747, W09319749, W09319751, W09325517, WO9402465, WO9406423, W09412461, WO9420455, W09422852, W09425437, W09427947, WO9500516, WO9501980, WO9503794, WO9504045, WO9504046, WO9505386, WO9508534, WO9509623, WO9509624, WO9509627, WO9509836, W09514667, WO9514680, W09514681, W09517392, W09517399, W09519362, WO9522520, W09524381, W09527692, W09528926, W09535281, W09535282, WO9600218, WO9601825, WO9602541, W09611917, DE3142982, DEI 116676, DE2162096, EP0293063, EP0463756, EP0482208, EP0579496, EP0667345 US6,331,543, US20050004222 (omfattende de som er beskrevet i formlene l-XIII og avsnittene 37-39, 85-0545 og 557-577) og WO9307124, EP0163965, EP0393500, EP0510562, EP0553174, WO9501338 og WO9603399. PDE5-inhibitorer som kan nevnes som eksempler er RX-RA-69, SCH-51866, KT-734, vesnarinon, zaprinast, SKF-96231, ER-21355, BF/GP-385, NM-702 og sildenafil (Viagra®). PDE4-inhibitorer som kan nevnes som eksempler er RO-20-1724, MEM 1414 (R1533/R1500; Pharmacia Roche), DENBUFYLLINE, ROLIPRAM, OXAGRELATE, NITRAQUAZONE, Y-590, DH-6471, SKF-94120, MOTAPIZONE, LIXAZINONE, INDOLIDAN, OLPRINONE, ATIZORAM, KS-506-G, DIPAMFYLLINE, BMY-43351, ATIZORAM, AROFYLLINE, FILAMINAST, PDB-093, UCB-29646, CDP-840, SKF-107806, PICLAMILAST, RS-17597, RS-25344-000, SB-207499,TIBENELAST, SB-210667, SB-211572, SB-211600, SB-212066, SB-212179, GW-3600, CDP-840, MOPIDAMOL, ANAGRELIDE, I BU Dl LAST, AMRINONE, PIMOBENDAN, CILOSTAZOL, QUAZINONE og N-(3,5-diklorpyrid-4-yl)-3-syklopropyhnetoksy4-difluormetoksybenzamid. PDE3-inhibitorer som kan nevnes som eksempler er SULMAZOLE, AMPIZONE, CILOSTAMIDE,
CARBAZERAN, PIROXIMONE, IMAZODAN, CI-930, SIGUAZODAN,
ADIBENDAN, SATERINONE, SKF-95654, SDZ-MKS-492, 349-U-85, EMORADAN, EMD-53998, EMD-57033, NSP-306, NSP-307, REVIZINONE, NM-702, WIN-62582 og WIN-63291, ENOXIMONE og MILRINONE. PDE3/4-hemmere som kan nevnes som eksempler er BENAFENTRINE, TREQUINSIN, ORG-30029, ZARDAVERINE, L-686398, SDZ-ISQ-844, ORG-20241, EMD- 54622 og TOLAFENTRINE. Andre PDE-hemmere omfatter: cilomilast, pentoksifyllin, roflumilast, tadalafil (Cialis®), teofyllin og vardenafil (Levitra (D), zaprinast (PDE5 spesielt).
Fremgangsmåter for behandling
Mange forskjellige forstyrrelser kan behandles med GC-C reseptor-agonister og midler som øker GMP-nivåer omfattende peptidene og agonistene ifølge oppfinnelsen.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for behandlig eller forebygging av kongestiv hjertesvikt. Slike agenser kan anvendes i kombinasjon med natriuretiske peptider (for eksempel atrial natriuretisk peptid, hjerne natriuretisk peptid eller C-type natriuretisk peptid), et diuretikum eller en inhibitor for angiotensinomdannende enzym.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for behandling eller forebygging av hypertrophia prostatae (BPH). Slike agenser kan anvendes i kombinasjon med ett eller flere agenser for behandling av BPH, for eksempel en 5-alfa reduktase-inhibitor (for eksempel finasterid) eller en alfa adrenergisk inhibitor (for eksempel doxazosin).
Peptidene og agonistene ifølge oppfinnelsen kan anvendes alene eller i kombinasjonsterapi for behandling, forebygging eller reduksjon av visceral smerte forbundet med en gastrointestinal forstyrrelse eller smerte forbundet med en annen lidelse.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for behandling eller forebygging av fedme-relaterte forstyrrelser (for eksempel forstyrrelser som er forbundet med, forårsaket av, eller følger av fedme). Eksempler på fedme-relaterte forstyrrelser omfatter forspising og bulimi, hypertensjon, diabetes, forhøyede konsentrasjoner av insulin i plasma og insulinresistens, dyslipidemi, hyperlipidemi, endometrie, bryst, prostata og colon kreft, osteoartritt, obstruktiv søvnapné, kolelitiasis, gallestener, hjertesykdom, unormale hjerterytmer og arrytmier, myokardinfarkt, kongestiv hjertesvikt, koronar hjertesykdom, plutselig død, slag, polycystisk ovariesyndrom, kraniofaryngeom, Prader-Willis syndrom, Frohlichs syndrom, GH-defisitte subjekter, normal variant kort høyde, Turners syndrom og andre patologiske tilstander som oppviser redusert metabolsk aktivitet eller en reduksjon i energiforbruk hos en hvilende som en prosentandel av total fettfri masse, for eksempel barn med akutt lymfoblastisk leukemi. Midlene ifølge oppfinnelsen kan anvendes for å redusere eller kontrollere kroppsvekt (eller fett) eller for å forebygge og/eller behandle fedme eller andre appetitt-relaterte forstyrrelser relatert til overskytende konsum av mat, etanol og andre appetittvekkende substanser. Midlene kan anvendes for å modulere lipidmetabolisme, redusere kroppsfett (for eksempel ved å øke utnytting av fett) eller redusere (eller undertrykke) apetitt (for eksempel ved å indusere metthet). Ytterligere eksempler på fedme-relaterte forstyrrelser er metabolsk syndrom, også kjent som syndrom X, insulinresistens syndrom, kjønnslig og reproduktiv dysfunksjon, slik som infertilitet, hypogonadisme hos menn og hirsutisme hos kvinner, gastrointestinal motilitetsforstyrrelser, slik som fedme-relatert gastroøsofagal refluks, respiratoriske forstyrrelser, slik som fedme-hypoventilering syndrom (Pickwick-syndromet), kardiovaskulære forstyrrelser, inflammasjon, slik som systemisk inflammasjon av vaskulaturen, arteriosklerose, hyperkolesterolemi, hyperurikemi, smerte i korsryggen, galleblæresykdom, gikt og kreft i nyrene. Midlene ifølge foreliggende oppfinnelse er også anvendelige for å redusere risikoen for sekundære følger av fedme, slik som å redusere risikoen for venstre ventrikkel-hypertrofi.
Peptidene og agonistene ifølge oppfinnelsen kan anvendes alene eller i kombinasjonsterapi for behandling eller forebygging av en gastrointestinal relatert forstyrrelse omfattende: kronisk intestinal pseudoobstruksjon (Ogilvies syndrom), colonisk pseudoobstruksjon, Crohns sykdom, dyspepsi (omfattende funksjonell dyspepsi eller non-ulcer dyspepsi), duodenogastrisk refluks, funksjonell tarmforstyrrelse, funksjonell gastrointestinal forstyrrelse, funksjonell kardialgi, gastroøsofagal reflukssykdom (GERD), gastrointestinale motilitetsforstyrrelser, gastroparese (for eksempel idiopatisk gastroparese), hypertrofisk pylorusstenose, inflammatorisk tarmsykdom, irritabel tarm-syndrom (IBS), postoperativ ileus og colitis ulcerosa. Peptidene og agonistene ifølge oppfinnelsen kan anvendes alene eller i kombinasjonsterapi for pasienter som lider av eller som er mottagelige for forstyrrelser i magetarm-kanalen relatert til skade i magetarm-kanalen som stammer fra støt eller kirurgisk intervensjon. Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for pasienter med risiko for eller som har bestemte sykdommer forbundet med hypomotilitet eller stasis i magetarm-kanalen. For eksempel er diabetisk neuropati, anorexia nervosa og aklorhydri ofte ledsaget av gastrisk hypomotilitet. Skade i i magetarm-kanalen etter kirurgisk intervensjon, for eksempel, kan resultere i vesentlig gastrisk stasis. Peptidene og agonistene kan administreres alene eller i kombinasjonsterapi til pasienter mottagelige for eller som har en fortyrrelse i magetarm-kanalen forbundet med diabetes (for eksempel diabetisk gastropati). Peptidene og agonistene ifølge oppfinnelsen kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle gastrointestinale forstyrrelserkarakterisert vedminst én av kvalme, oppkasting, kardialgi, postprandial discomfort, diaré, konstipasjon, indigestion eller relatere symptomer. Peptidene og agonistene ifølge oppfinnelsen kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle gastrointestinale forstyrrelser forbundet med minst én av diabetes, anorexia nervosa, bulimi, aklorhydri, akalasi, anal fissur, irritabel tarm-syndrom, intestinal pseudoobstruksjon, skleroderma og gastrointestinal skade.
Peptidene og agonistene ifølge oppfinnelsen kan anvendes for å forebygge og/eller behandle konstipasjon (for eksempel konstipasjon forbundet med anvendelse av et terapeutisk middel; konstipasjon forbundet med en neuropatisk, metabolsk eller endokrin forstyrrelse (omfattende autonom neuropati, Chagas sykdom, cystisk fibrose, diabetes mellitus, Hirschsprungs sykdom, hypertyroidisme, hypokalsemi, hypotyroidisme, Multippel sklerose, neurofibromatose, Parkinsons sykdom og ryggmargskader); postkirurgisk konstipasjon (postoperativ ileus); konstipasjon forbundet med en gastrointestinal forstyrrelse; idiopatisk konstipasjon (funksjonell konstipasjon eller langsom transit konstipasjon); konstipasjon forbundet med anvendelse av analgetiske medikamenter (for eksempel opoid indusert konstipasjon); konstipasjon forbundet med anvendelse av andre midler (for eksempel antihypertensiver, anticonvulsiva, antidepressive midler, krampestillende og antipsykotiske midler); megacolon; og kronisk konstipasjon).
Peptidene og agonistene ifølge oppfinnelsen kan anvendes for å behandle redusert intestinal motilitet, langsom fordøyelse eller langsom magetømming. Peptidene og agonistene kan anvendes for å lindre ett eller flere symptomer på IBS (oppblåsthet, smerte, konstipasjon), GERD (syrerefluks inn i øsofagus), duodenogastrisk refluks, funksjonell dyspepsi eller gastroparese (kvalme, oppkasting, oppblåsthet, forsinket magetømming) og andre forstyrrelser beskrevet heri.
Peptidene og agonistene ifølge oppfinnelsen kan anvendes for å forøke intestinal motilitet og for å forebygge og/eller behandle gastrointestinal ubevegelighet og andre tilstander som etterspør avføringsmidler eller behandling for bløtgjøring av avføring. Gastrointestinal ubevegelighet kan omfatte konstipasjon, og omfatter også forsinket oral cecal transittid, uregelmessig Taxation, og andre relaterte gastrointestinale motilitetdysfunksjoner omfattende retensjon. Retensjon er en tilstand hvor en stor masse av tørr, hard avføring utvikles i rektum, ofte på grunn av kronisk konstipasjon. Denne massen kan være så hard at den ikke kan utskilles. Subjektene rammet av konstipasjon eller gastrointestinal immotilitet kan være motstandsdyktige mot behandling med avføringsmiddelog/eller behandling for bløtgjøring av avføring.
Peptidene kan anvendes for å behandle eller forebygge kreft, prekankrøs vekst eller metastatisk vekst. De kan for eksempel anvendes for å forhindre eller behandle: kolorektal/lokal metastatisk kolorektal kreft, tarmpolypper, kreft i magetarmkanalen, lungekreft, kreft eller prekankrøs vekst eller metastatisk vekst av epitelceller, polypper, bryst, kolorektal, lunge, ovarie, pankreatisk, prostata, nyre, mage, blære, lever, øsofagus og testikkelkarsinom, karsinom (for eksempel basalcelle, baso-skvamøs, Brown-Pearce, duktalt karsinom, Ehrlich tumor, Krebs, Merkelcelle, oat eller non-oat, småcellet, papillo, bronkiolo, plateepitel, T-celle, Walker), leukemi (for eksempel B-celle, T-celle, HTLV, akutt eller kronisk lymfe, mastcelle, myeloid), histiocytonia, retikulose, Hodgkins sykdom, non-Hodgkin lymfom, plasmacytom, retikuloendoteliose, adenom, adenokarsinom, adenofibrom, adenolymfom, ameloblastom, angiokeratom, angiolymfoid hyperplasi med eosinofili, skleroserende angiom, angiomatose, apudom, branchionia, malign karsinoid syndrom, karsinoid hjertesykdom, karsinosarkom, cementoma, kolangiom, kolesteatom, kondrosarkom, kondroblastom, kondrosarkom, kordom, choristom, kraniofaryngeom, chrondrorna, sylindrom, cystadenokarcinom, cystadenom, cystosarconia phyllodes, dysgenninoma, ependymom, Ewing-tumor, fibrom, fibrosarkom, kjempecelletumor i benvev, ganglioneurom, glioblastom, glomangiom, granulosacelletumor, gynandroblastom, hamartom, hemangioendoteliom, hemangiom, hemangiopericytom, hemangiosarkom, hepatom, øycelletumor, Kaposis sarkom, leiomyom, leiomyosarkom, leukosarkom, Leydigcelle-tumor, lipom, liposarkom, lymphaugioma, lymfangiomyom, lymfangiosarkom, medulloblastom, meningiom, mesenkymom, mesonefrom, mesoteliom, myoblastom, myom, myosarkom, myksom, myksosarkom, neurilemmom, neurom, neuroblastom, neuroepiteliom, neurofibrom, neurofibromatose, odontoblastom, osteom, osteogent sarkom, papillom, paragangliom, paraganglionia, nonchroinaffin, pinealom, rabdomyom, rabdomyosarkom, androblastom, teratom, tekacelletumor og andre sykdommer hvor celler er blitt dysplastiske, immortaliserte eller transformerte.
Peptidene og agonistene kan anvendes for behandling eller forebygging av: Familiær adenomatøs polypose (FAP) (autosomal dominant syndrom) som går forut for cancer coli, hereditær nonpolypose colorectalcancer (HNPCC), og nedarvet autosomal dominant syndrom.
For behandling eller forebygging av kreft, prekankrøs vekst eller metastatisk vekst kan peptidene og agonistene anvendes i kombinasjonsterapi med stråling eller kjemoterapeutiske midler, en inhibitor for en cGMP-avhengig fosfodiesterase eller en selektiv syklooksygenase-2-hemmer. Mange forskjellige selektive sykloksygenase-2-hemmere er beskrevet i US20010024664, U.S. Pat. Nr.. 5,380,738, U.S. Pat. Nr. 5,344,991, U.S. Pat. Nr. 5,393,790, U.S. Pat. Nr. 5,434,178, U.S. Pat. Nr. 5,474,995, U.S. Pat. Nr. 5,510,368, WO02/062369, WO 96/06840, WO96/03388, WO96/03387, WO 96/19469, WO 96/25405, WO 95/15316, WO 94/15932, WO 94/27980, WO 95/00501, WO 94/13635, WO 94/20480 og WO 94/26731. [Pyrazol-1-yl]benzensulfonamider har også blitt beskrevet som inhibitorer av sykloksygenase-2.
Peptidene og agonistene kan anvendes ved behandlng eller forebygging av inflammasjon. Følgelig kan de anvendes alene eller i kombinasjon med en hemmer av cGMP-avhengig fosfodiesterase eller en selektiv syklooksygenase-2-hemmer for behandlng av: inflammasjon av organ, IBD (for eksempel Crohns sykdom, colitis ulcerosa), astma, nefritt, hepatitt, pankreatitt, bronkitt, cystisk fibrose, iskemiske tarmsykdommer, inflammasjoner/allergier i tarmen, cøliaki, proktitt, eosinofil gastroenteritt, mastocytose og andre inflammatoriske forstyrrelser. Peptidene og agonistene ifølge oppfinnelsen kan anvendes alene eller i kombinasjonsterapi ved behandling eller forebygging av inflammasjon i magetarm-kanalen (for eksempel inflammasjon forbundet med en gastrointestinal forstyrrelse, infeksjon i magetarm-kanalen, eller annen forstyrrelse).
Peptidene og agonistene kan også anvendes for å behandle eller forebygge insulin-relaterte forstyrrelser, foreksempel: II diabetes mellitus, hyperglykemi, fedme, forstyrrelser forbundet med forstyrrelser i glukose eller elektrolytt-transport og insulinsekresjon i celler, eller endokrine forstyrrelser. De kan også anvendes ved insulinresistens behandling og postkirurgisk og ikke-postkirurgisk reduksjon i insulinfølsomhet.
Peptidene og agonistene kan anvendes for å forebygge og/eller behandle pulmonale og respiratorisk relaterte forstyrrelser, omfattende, inhalasjon, ventilasjon og mukus-sekresjon forstyrrelser, pulmonal hypertensjon, kronisk obstruksjon av kar og luftveier og irreversible obstruksjoner av kar og bronkier. Et middel kan administreres for behandling av bronkospasme, for indusering av bronkodilatasjon for behandling av kronisk obstruktiv pulmonal sykdom (omfattende kronisk bronkitt med normal luftstrøm), for behandling av astma (omfattende bronkial astma, intrinsisk astma, ekstrisisk astma, kronisk eller innbitt astma (for eksempel sen astma og overfølsomhet i luftveiene), astma indusert av støv, allergen-indusert astma, virusindusert astma, kuldeindusert astma, astma indusert av forurensning og astma indusert av anstrengelse) og for behandling av rinitt (omfattende akutt-, allergisk, hatrophic rinitt eller kronisk rinitt (slik som rhinitis caseosa, hypertrof rinitt, rhinitis purulenta, rhinitis sicca), rhinitis medikamentosa, membranøs rinitt (omfattende croupous, fibrinøs og pseudomembranøs rinitt), scrofulous rinitt, perennial allergisk rinitt, periodisk rinitt (omfattende rhinitis nervosa (høysnue) og vasomotorisk rinitt). Peptidene kan også være anvendelig ved behandling av øyesykdom av "tørr type" og kronisk sinusitt. Peptidene ifølge oppfinnelsen kan også anvendes for å forebygge og/eller behandle forstyrrelserkarakterisert vedakutt pulmonal vasokonstriksjon slik som kan følge av pneumoni, traumatisk skade, aspirasjon eller inhalasjonsskade, fettembolisme i lungene, acidose inflammasjon i lungene, adult respiratorisk distress syndrom, akutt pulmonalt ødem, akutt fjellsyke, post hjertekirurgi, akutt pulmonal hypertensjon, persistent pulmonal hypertensjon hos nyfødte, perinatalt aspirasjonssyndrom, hyalin membran-sykdom, akutt pulmonal tromboembolisme, herapin-protamin reaksjoner, sepsis, status astmaticus eller hypoksi (omfattende iatrogen hypoksi) og andre former for reversibel pulmonal vasokonstriksjon. Slike pulmonale forstyrrelser er ogsåkarakterisert vedinflammasjon i lungene omfattende de som er forbundet med migrering inn i lungene av ikke-residente celletyper omfattende de forskjellige subklassene av leukocytter. Også omfattet i de respiratoriske forstyrrelsene medregnet er: bulløs sykdom, hoste, kronisk hoste forbundet med inflammasjon eller iatrogen indusert, luftveiskonstriksjon, duehandlersykdom, eosinofil bronkitt, astmatisk bronkitt, kronisk bronkitt med luftveisobstruksjon (kronisk obstruktiv bronkitt), eosinofil lungesykdom, emfysem, "farmer's lung", allergiske øyesykdommer (omfattende allergisk konjunktivitt, vernal konjunktivitt, vernal keratokonjunktivitt giant papillar/conjunctivitis), idiopatisk pulmonal fibrose, cystisk fibrose, diffuse pan bronkolitt og andre sykdommer som erkarakterisertved inflammasjon i lungene og/eller overdreven sekresjon av mukosa. Andre fysiologiske hendelser som er omfattet hvilke er medregnet å forebygges, behandles eller kontrolleres omfatter blodplateaktivering i lungene, kroniske inflammatoriske sykdommer i lungene som fører til interstitiell fibrose, slik som interstitiell lungesykdom (ILD) (for eksempel, idiopatisk pulmonal fibrose eller ILD forbundet med reumatoid arttritt, eller andre autoimmune tilstander), kronisk obstruktiv pulmonal sykdom (KOLS) (slik som irreversibel KOLS), kronisk sinusitt, fibroid lunge, hypersensitivitet lungesykdommer, hypersensitivitetpneumonitt, idiopatisk interstitiell pneumoni, nasal kongestion, nasal polypose og otitis media.
Peptidene og agonistene kan anvendes alene eller i kombinasjonterapi for å forebygge eller behandle: retinopati, neuropati, diabetisk angiopati og ødemdannelse
Peptidene og agonistene kan anvendes alene eller i kombinasjonterapi for å forebygge eller behandle neurologiske forstyrrelser, for eksempel, hodepiner, migrener, angst, stress, kognitive forstyrrelser, cerebral iskemi, hjernetraumer, bevegelsesforstyrrelser, agresjon, psykose, anfall, panikkangrep, hysteri, søvnlidelser, depresjon, schizoaffektive lidelser, søvnapné, oppmerksomhetssvikt-syndromer, hukommelsestap, demens, hukommelse og læringsforstyrrelser som diskutert i Moncada og Higgs 1995 FASEB J. 9:1319-1330; Severina 1998 Biochemistry 63:794; Lee et al. 2000 PNAS 97:10763-10768; Hobbs 1997 TIPS18:484-491; Murad 1994 Adv. Pharmacol. 26:1-335; og Denninger et al. 1999 Biochim. Biophys. Acta 1411:334-350 og narkolepsi. De kan også anvendes som et sedativ.
Peptidene og detekterbart merkede peptider og agonister kan anvendes som markører for å identifisere, detektere, foranstalte eller diagnostisere sykdommer og tilstander i tynntarmen inkludert, uten begrensning: Crohns sykdom, colitt, inflammatorisk tarmsykdom, tumorer, benigne tumorer, slik som benigne stromale tumorer, adenom, angiom, adenomatøse (pedulerende og sessile) polypper, malignante, karsinoide tumorer, endokrin celle-tumorer, lymfom, adenokarsinom, karsinom i forreste del, i midtre del og i bakerste del av tarmen, gastroinstestinal stromal tumor (GIST), slik som leiomyom, cellulært leiomyom, leiomyoblastom, og leiomyosarkom, gastrointestinal autonom nerve-tumor, malabsorpsjonssyndromer, cøliak sykdommer, divertikulose, Meckel's divertikkel, colon divertikkel, megacolon, Hirschsprungs sykdom, irritabel tarm-syndrom, mesenterisk iskemi, iskemisk kolitt, kolorektal cancer, colon polypose, polypp syndrom, intestinal adenokarsinom, Liddles syndrom, Brody myopati, infantil konvulsjon og koreoatetose.
Peptidene og agonistene kan konjugeres til et annet molekyl (for eksempel et diagnostisk eller terapeutisk molekyl) for å målrette celler som bærer GCC-reseptoren, for eksempel, cystisk fibrose lesjoner og spesifikke celler som bekler fordøyelseskanalen. Følgelig kan de anvendes for å målrette radioaktive grupper eller terapeutiske grupper til tarmen for å bistå ved avbildning og diagnostisering eller behandling av kolorektal/metastatisk eller lokal kolorektal cancer og til å levere normale kopier av p53 tumorsuppressor-genet til fordøyelseskanalen. Peptidene og agonistene kan også anvendes for å øke antallet av GC-C-molekyler på overflaten av en celle. I noen former er cellen en metastatisk kolorektal kreftcelle. I én form er peptidet eller agonisten terapeutisk konjugert til et andre middel. I visse former kan det andre midlet være radioaktivt eller radiostabilt. I visse former kan det andre midlet være valgt fra gruppen bestående av en forbindelse som forårsaker celledød, en forbindelse som hemmer celledeling, en forbindelse som induserer differensiering av celler, et kjemoterapeutisk middel, et toksin og et radiosensibiliserende middel. I visse former kan det andre midlet være valgt fra gruppen bestående av: metotreksat, doksorubicin, daunorubicin, cytosinarabinosid, etoposid, 5-4 fluorouracil, melfalan, klorambucil, cis-platin, vindesin, mitomycin, bleomycin, purotionin, makromomycin, 1,4-benzoquinonderivater, trenimon, ricin, ricin A-kjede, Pseudomonas eksotoksin, difteritoksin, Clostridium perfringens fosfolipase C, bovin pankreas ribonuklease, kermisbær antiviralt protein, abrin, abrin A-kjede, kobra venom faktor, gelonin, saporin, modeccin, viscumin, volkensin, nitroimidazol, metronidazol og misonidazol.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle lidelser i det indre øret, for eksempel, for å forebygge og/eller behandle Menieres sykdom (inkludert symptomer på sykdommen slik som svimmelhet, hørselstap, tinnitus, fornemmelse av fullhet i øret), Mal de débarquement syndrom, otitis externa, otitis media, otoré, akutt mastoiditt, otosklerose, smerte i øret, blødning i øret, øreinflammasjon, Lermoyez syndrom, vestibulær neuronitt, benign paroksystisk posisjonsvertigo (BPPV), herpes zoster oticus, Ramsay Hunts syndrom, herpes, labyrintitt, purulent labyrintitt, perilymfefistel, presbyakusis, ototoksisitet (omfattende medikament-indusert ototoksisitety), neuromia (omfattende akustisk neurom), aerotitis media, infeksiøs myringitt, bulløs myringitt, plateepitelkreft, basalcellekarsinom, prekankrøse tilstander i øret, non-chromaffin paragangliom, kjemodektom, glomus jugulare tumorer, glomus tympanicum tumorer, perichondritt, øre eczematoid dermatitt, malign ekstern otitt, subperichondrie hematom, ceruminom, impacted cerumen, fettcyster, osteoma, keloider, otalgia, tinnitus, tympanmembran-infeksjon, tympanitt, byll i øret, petrositt, konduktiv og sensorineural hørselsnedsettelse, epidural byll, lateral sinustrombose, subdural empyem, otitichydrocephalus, Dandy's syndrome, bulløs myringitt, diffus ekstern otitt, fremmedlegemer, keratosis obturans, otic neoplasm, otomykose, traume, akutt barotitis media, akutt obstruksjon av øretrompeten, postkirurgisk otalgia, kolesteatom, infeksjoner relatert til ørekirurgi-prosedyre, og komplikasjoner forbundet med hvilke som helst av nevnte forstyrrelser. Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å opprettholde væskehomeostase i det indre øret, neuronitt (omfattende viral neuronitt), ganglionitis, kneleddet.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle forstyrrelser forbundet med væske og natriumretensjon, for eksempel sykdommer i elektrolytt-vann/elektrolytt-transportsystemet i nyrene, tarmen og urogenitalsystemet, kongestiv hjertesvikt, hypertensjon, hypotensjon, saltavhengige former av høyt blodtrykk, hepatisk ødem, og lever cirrhose. I tillegg kan de anvendes for å lette diurese eller kontrollere tarmvæske. Peptidene og agonistene kan også anvendes for å behandle forstyrrelser hvor det er unormal proliferasjon av epitelceller i nyrene (for eksempel som i tilfelle av nyrekreft).
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle nyresykdom. "Nyresykdom" omfatter nyresvikt (omfattende akutt nyresvikt), renal utilstrekkelighet, nefrotisk ødem, glomerulonefritt, pyelonefritt, nyresvikt, kronisk nyresvikt, nefritt, nefrose, azotemia, uremi, immun nyresykdom, akutt nefrittsyndrom, hurtig progressiv nefrittsyndrom, nefrotisk syndrom, Bergers syndrom, kronisk nefritt/proteinuri syndrom, tubulointerstital sykdom, nefrotoksiske forstyrrelser, nyreinfarkt, ateroembolisk nyresykdom, renal kortikal nekrose, malign nefroangiosklerose, nyrevene-trombose, renal tubulær acidose, renal glukosuri, nefrogen diabetes insipidus, Bartters syndrom, Liddle's syndrom, polycystisk nyresykdom, medullær cystisk sykdom, medullær svampnyre, arvelig nefritt og nagl-patella syndrom, sammen med hvilken som helst sykdom eller forstyrrelse relatert til nyresystemet og relaterte forstyrrelser, så vel som symptomer indikative for, eller relatert til, renal eller nyresykdom og relaterte forstyrrelser.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge eller behandle polycystisk nyresykdom. Polycystisk nyresykdom" "PKD"
(også kalt "polycystisk renal sykdom") refererer til en gruppe av forstyrrelserkarakterisert vedet stort antall cyster spredt gjennom hele de dramatisk forstørrede nyrene. Den resulterende utviklingen av cyster fører til svekkelse av nyrefunksjon og kan eventuelt forårsake nyresvikt. "PKD" omfatter spesielt autosomal dominant polycystisk nyresyksdom (ADPKD) og recessiv autosomal recessiv polycystisk nyresykdom (ARPKD), i alle utviklingstrinn, uansett den underliggende årsaken.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle forstyrrelser forbundet med bikarbonat sekresjon, for eksempel, cystisk fibrose.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle forstyrrelser forbundet med gallesekresjon. I tillegg kan de anvendes for å lette eller kontrollere klorid og gallevæske sekresjon i galleblæra.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle forstyrrelser forbundet med regenerering av leverceller. Dette kan omfatte administrering av peptidene og agonister til mottagere av levertransplantater og til pasienter med medikament eller alkoholindusert leverskade. Videre kan peptidene og agonistene være anvendelige for å behandle leverskade som i tilfelle av virusmediert hepatitt. Peptidene og agonistene kan anvendes alene eller i kombinasjon for å forebygge og/eller behandle leverabscess, leverkreft (enten primær eller metastatisk), cirrhose (slik som cirrhose forårsaket av alkoholforbruk eller primær biliær cirrhose), amøbisk leverabscess, autoimmun hepatitt, biliær atresi, koksidioidomykose disseminert, 5 agens (hepatitt 5), hemokromatose, hepatitt a, hepatitt b, hepatitt c, eller hvilken som helst annen akutt, subakutt, fulminant eller kronisk hepatitt av viral, metabolsk eller toksisk etiologi, hepatocellulært carsinom, pyogen leverabscess, Reyes syndrom, skleroserende kolangitt, Wilsons sykdom, medikamentindusert hepatotoksisitet, eller fulminant eller akutt leversvikt. Peptidene og agonistene kan anvendes for å stimulere hepatisk regenerasjon etter kirurgisk hepatektomi.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle myokardinfarkt, diastolisk dysfunksjon, angina pektoris, stabil, ustabil og variant (Prinzmetal) angina, aterosklerose, trombose, endotel dysfunksjon, hjerteødem, slag, tilstander av redusert blodkar åpenhet, for eksempel post perkutan transluminal coronar angioplastikk (post-PTCA) og perifer vaskulær sykdom.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle glaukom.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle immunsvikt.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle blæreavløpshindring ("bladder outlet obstruction") og inkontinens.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle mannlig (for eksempel erektil dysfunksjon) eller kvinnelig seksuell dysfunksjon, partus prematurus, og dysmenoré. I visse utførelsesformer kan de anvendes i kombinasjon med en fosfodiesterase-hemmer.
Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å forebygge og/eller behandle osteopeni forstyrrelser (bentap forstyrrelser). "Bentap forstyrrelser" omfatter tilstander og sykdommer hvori hemmingen av bentap og/eller fremming av bendannelse er øsnkelig. Av slike tilstander og sykdommer er osteoporose, osteomyelitt, Pagets sykdom (osteitis deformans), periodontitt, hyperkalsemi, osteonekrose, osteosarkom, osteolyic metastase, familial expansile osteolysis, prosthetic loosening, periprostetisk osteolyse, bentap som ledsager reumatoid artritt og cleiodocranial dysplasi (CCD). Osteoporose omfatter primær osteoporose, endokrin osteoporose (hypertyroidisme, hyperparatyroidisme, Cushings syndrom og akromegali), arvelig og kongenital form av osteoporose
(osteogenesis imperfecta, homocystinuri, Menkes syndrom og Rile-Day syndrom)
og osteoporose som skyldes immobilisering av extremitiesosteomyelitt, eller en infeksjiøs skade i ben som fører til bentap. Peptidene og agonistene kan anvendes alene eller i kombinasjonsterapi for å stimulere benregenerering. Benregenerering kan være etter rekonstruksjon av bendefekter i cranio-maxillofacial kirurgi, eller etter et implantat inn i ben, for eksempel et tannimplantat, ben støtte-implantat eller protese. Benregenereringen kan også være etter en benfraktur.
Peptidene som er homologe med ST-peptider kan anvendes som immunogener for å behandle og/eller forebygge ett eller flere symptomer på sykdommer forbundet med traveler's diaré. Metodene beskrevet i US20040146534, US4220584, US4285391, US5182109, US4603049, US4545931, US4886663 og WO08402700 kan anvendes på lignende måte for å danne immunogener omfattende peptidene ifølge oppfinnelsen.
Claims (18)
1. Polypeptid,karakterisert veda t det består av aminosyresekvensen: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (Sekv.lD Nr:81) eller et farmasøytisk akseptabelt salt derav.
2. Polypeptid ifølge krav 1,karakterisert vedat polypeptidet aktiverer guanylat cyklase C reseptoren.
3. Farmasøytisk sammensetning,karakterisert vedat den omfatter et polypeptid ifølge et hvilket som helst av kravene 1-2.
4. Anvendelse av et polypeptid ifølge et hvilket som helst av kravene 1-3, eller farmasøytisk sammensetning ifølge krav 3 for fremstilling av et medikament for behandling av en gastrointestinal forstyrrelse.
5. Anvendelse ifølge krav 4, hvor den gastrointestinale forstyrrelsen er en gastrointestinal bevegelsesforstyrrelse.
6. Anvendelse ifølge krav 4, hvor den gastrointestinale forstyrrelsen er valgt fra gruppen bestående av: irritabel tarmsyndrom, konstipasjon, en funksjonell gastrointestinal forstyrrelse, gastroesofagus reflukssykdom, funksjonell halsbrann, dyspepsi, gastroparese, kronisk intestinal pseudo-obstruksjon, kolon pseudo-obstruksjon, Chron's sykdom, ulcerativ kolitt og inflammatorisk tarmsykdom.
7. Anvendelse ifølge krav 6, hvor den gastrointestinale forstyrrelsen er konstipasjon.
8. Anvendelse ifølge krav 7, hvor konstipasjonen er kronisk konstipasjon, idiopatisk konstipasjon, grunnet postoperativ tarmslyng, eller forårsaket av opiatbruk.
9. Anvendelse ifølge krav 4, hvor den gastrointestinale forstyrrelsen er irritabel tarmsyndrom.
10. Anvendelse ifølge krav 9, hvor det irritable tarmsyndromet er alternerende irritabel tarmsyndrom eller konstipasjon-predominant irritabel tarmsyndrom.
11. Anvendelse av et polypeptid ifølge et hvilket som helst av kravene 1-2, eller den farmasøytiske sammensetningen ifølge krav 4 for fremstilling av et medikament for å øke den gastrointestinale motiliteten.
12. Anvendelse ifølge et hvilket som helst av kravene 4-11, hvor medikamentet administreres oralt.
13. Polypeptid ifølge kravene 1-2 eller farmasøytisk sammensetning ifølge krav 4,karakterisert veda t det er for behandling av en gastrointestinal forstyrrelse.
14. Polypeptid eller farmasøytisk sammensetning ifølge krav 13,karakterisert vedat den gastrointestinale forstyrrelsen er valgt fra gruppen bestående av: irritabel tarmsyndrom, konstipasjon, en funksjonell gastrointestinal forstyrrelse, gastroesofagus reflukssykdom, funksjonell halsbrann, dyspepsi, gastroparese, kronisk intestinal pseudo-obstruksjon, pseudo-obstruksjon, Chron's sykdom, ulcerativ kolitt og inflammatorisk tarmsykdom.
15. Polypeptid eller farmasøytisk sammensetning ifølge krav 14,karakterisert vedat den gastrointestinale forstyrrelsen er konstipasjon.
16. Polypeptid eller farmasøytisk sammensetning ifølge krav 15,karakterisert vedat konstipasjonen er kronisk konstipasjon, idiopatisk konstipasjon, grunnet postoperativ tarmslyng eller forårsaket av opiatbruk.
17. Polypeptid eller farmasøytisk sammensetning ifølge krav 14,karakterisert vedat den gastrointestinale forstyrrelsen er irritabel tarmsyndrom.
18. Polypeptid eller farmasøytisk sammensetning ifølge krav 17,karakterisert vedat det irritable tarmsyndromet er alternerende irritabel tarmsyndrom eller konstipasjon-predominant irritabel tarmsyndrom.
Applications Claiming Priority (5)
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US10/796,719 US7304036B2 (en) | 2003-01-28 | 2004-03-09 | Methods and compositions for the treatment of gastrointestinal disorders |
US10/845,895 US20060281682A1 (en) | 2003-01-28 | 2004-05-14 | Methods and compositions for the treatment of gastrointestinal disorders |
US10/899,806 US7371727B2 (en) | 2003-01-28 | 2004-07-27 | Methods and compositions for the treatment of gastrointestinal disorders |
US11/054,071 US7772188B2 (en) | 2003-01-28 | 2005-02-08 | Methods and compositions for the treatment of gastrointestinal disorders |
PCT/US2005/007752 WO2005087797A1 (en) | 2004-03-09 | 2005-03-08 | Methods and compositions for the treatment of gastrointestinal disorders |
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NO20064121L NO20064121L (no) | 2006-11-22 |
NO335730B1 true NO335730B1 (no) | 2015-02-02 |
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NO20064121A NO335730B1 (no) | 2004-03-09 | 2006-09-13 | Polypeptid og farmasøytisk sammensetning, samt anvendelse derav. |
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US (1) | US7772188B2 (no) |
EP (2) | EP1730172A4 (no) |
JP (2) | JP2008501310A (no) |
KR (1) | KR101202727B1 (no) |
CN (2) | CN102020704A (no) |
AU (1) | AU2005222387B2 (no) |
BR (1) | BRPI0508558A (no) |
CA (1) | CA2558050C (no) |
IL (1) | IL177772A0 (no) |
MX (1) | MXPA06010205A (no) |
NO (1) | NO335730B1 (no) |
NZ (1) | NZ549519A (no) |
SG (1) | SG153824A1 (no) |
WO (1) | WO2005087797A1 (no) |
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-
2005
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- 2005-03-08 CN CN2010105277281A patent/CN102020704A/zh active Pending
- 2005-03-08 EP EP05732019A patent/EP1730172A4/en not_active Withdrawn
- 2005-03-08 CA CA2558050A patent/CA2558050C/en active Active
- 2005-03-08 NZ NZ549519A patent/NZ549519A/en unknown
- 2005-03-08 CN CNA200580014557XA patent/CN101010335A/zh active Pending
- 2005-03-08 AU AU2005222387A patent/AU2005222387B2/en active Active
- 2005-03-08 WO PCT/US2005/007752 patent/WO2005087797A1/en active Application Filing
- 2005-03-08 BR BRPI0508558-6A patent/BRPI0508558A/pt not_active Application Discontinuation
- 2005-03-08 SG SG200904060-1A patent/SG153824A1/en unknown
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- 2005-03-08 KR KR1020067020883A patent/KR101202727B1/ko active IP Right Grant
- 2005-03-08 EP EP09154673.9A patent/EP2088154B1/en not_active Revoked
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2006
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- 2006-09-13 NO NO20064121A patent/NO335730B1/no unknown
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CN101010335A (zh) | 2007-08-01 |
MXPA06010205A (es) | 2007-03-15 |
EP2088154B1 (en) | 2017-12-13 |
US20090062207A1 (en) | 2009-03-05 |
EP1730172A4 (en) | 2009-01-14 |
CA2558050C (en) | 2013-11-05 |
US7772188B2 (en) | 2010-08-10 |
AU2005222387B2 (en) | 2010-12-02 |
NO20064121L (no) | 2006-11-22 |
EP2088154A1 (en) | 2009-08-12 |
JP2008501310A (ja) | 2008-01-24 |
KR101202727B1 (ko) | 2012-11-20 |
CN102020704A (zh) | 2011-04-20 |
JP5559087B2 (ja) | 2014-07-23 |
IL177772A0 (en) | 2006-12-31 |
EP1730172A1 (en) | 2006-12-13 |
KR20070007332A (ko) | 2007-01-15 |
SG153824A1 (en) | 2009-07-29 |
JP2011152140A (ja) | 2011-08-11 |
NZ549519A (en) | 2010-03-26 |
CA2558050A1 (en) | 2005-09-22 |
WO2005087797A1 (en) | 2005-09-22 |
BRPI0508558A (pt) | 2007-08-07 |
AU2005222387A1 (en) | 2005-09-22 |
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