HRP960045A2 - Combination therapy for hiv infection - Google Patents
Combination therapy for hiv infection Download PDFInfo
- Publication number
- HRP960045A2 HRP960045A2 HR08/382,113A HRP960045A HRP960045A2 HR P960045 A2 HRP960045 A2 HR P960045A2 HR P960045 A HRP960045 A HR P960045A HR P960045 A2 HRP960045 A2 HR P960045A2
- Authority
- HR
- Croatia
- Prior art keywords
- combination
- hiv
- compound
- treatment
- reverse transcriptase
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
Područje tehnike
Kombinacija ovog izuma korisna je za inhibiranje proteaze HIV-a, za inhibiranje obrnute transkriptaze HIV-a, u liječenju infekcije HIV-om i u liječenju AIDS-a i/ili ARC-a (kompleks pridružen AIDS-u, AIDS-related complex), u obliku spojeva, farmaceutski prihvatljivih soli ili estera (kada je to pogodno), sastojaka farmaceutskih pripravaka, samih ili u kombinaciji s drugim protuvirusnim ili protuinfektivnim tvarima, imuno modulatorima, antibioticima ili cjepivima. Također su opisani postupci liječenja AIDS-a, postupci sprečavanja infekcije HIV-om i postupci liječenja infekcije HIV-om.
Stanje tehnike
Retrovirus nazvan virusom humane imunodeficijencije (HIV) uzročnik je složene bolesti koja uključuje progresivno razaranje imunosnog sustava (sindrom stečene imunodeficijencije; AIDS) kao i propadanje središnjeg i perifernog živčanog sustava. Ovaj je virus prije bio poznat kao LAV, HTLV-III ili ARV. Zajedničko obilježje umnožavanja virusa je opsežna posttranslacijska proizvodnja poliproteina prekursora pomoću proteaze kodirane virusom, čime nastaju zreli virusni proteini potrebni za sastavljanje virusa i njegovu funkciju, inhibicija ovog procesa spriječit će proizvodnju virusa uobičajene infektivnosti. Na primjer, Kohl, N.E. i sur.,Proc. Nat'l. Acad. Sci., 85, 4686 (1988), pokazali su da genetička inaktivacija proteaze kodirane HIV-om ima za posljedicu proizvodnju nezrelih, neinfektivnih virusnih čestica. Ovi rezultati pokazuju da inhibicija HIV proteaze predstavlja uspješan postupak za liječenje AIDS-a i sprečavanje ili liječenje infekcije HIV-om.
Određivanje nukleotidnog slijeda HIV-a pokazuje prisutnost pol gena u jednom otvorenom okviru čitanja (engl. open reading frame) [Ratner, L. I sur., Nature, 313, 277 (1985)]. Homolognost aminokiselinskog slijeda predstavlja dokaz da pol slijed kodira obrnutu transkriptazu, endonukleazu i proteazu HIV-a (Toh, H. I sur., EMBO J., 1267 (1985); Power, M.D. i sur., Science, 231, 1567 (1986); Pearl, L.H. i sur., Nature, 329, 351 (1987)).
Spoj opisan i nazvan "Spoj J'' u EPO 541,168, objavljenom 12. Svibnja 1993, moćan je inhibitor proteaze HIV-a i koristan u sprečavanju infekcije HIV-om, liječenju infekcije HIV-om i liječenju AIDS-a i ARC-a, a bez značajnih nuspojava ili toksičnosti:
[image]
ili njegove farmaceutski prihvatljive soli.
SPOJ J
Jedan od temeljnih i trajnih problema u liječenju AIDS-a je sposobnost virusa da razvije otpornost na pojedinačne terapijske pripravke korištene u suzbijanju bolesti. U svrhu rješavanja tog problema, autori ovog patenta otkrili su kombinirano liječenje AIDS-a.
Autori pokazuju da je kombinacija spojeva ovog izuma korisna u liječenju infekcije HIV-om.
U ovom izumu, autori su zajednički primjenjivali moćni inhibitor proteaze HIV-a, Spoj J, i inhibitor obrnute transkriptaze HIV-a 3TC. Izborno je u kombinaciju dodavana i treća komponenta, i to nukleozidni inhibitor obrnute transkriptaze HIV-a, kao što je AZT, ddI ili ddC. Ovakvo kombinirano liječenje je postupak za povećavanje učinkovitosti u liječenju AIDS-a I sprečavanje razvoja otpornosti na pojedinačne lijekove.
Izlaganje biti izuma
Ovaj izum uključuje kombinaciju Spoja J i nukleozidnog analoga inhibitora obrnute transkriptaze HIV-a 3TC, i, izborno, nukleozidnog inhibitora obrnute transkriptaze HIV-a, odabranog između AZT, ddI i ddC, ili njihove farmaceutski prihvatljive soli i estere.
Opsežan opis izuma i preporučenih načina primjene
Ovaj se izum odnosi na kombinaciju određenih spojeva ili njihovih farmaceutski prihvatljivih soli radi inhibiranja proteaze HIV-a, inhibiranja obrnute transkriptaze HIV-a, sprečavanja ili liječenja infekcije HIV-om i liječenja posljedičnog sindroma stečene imunodefinicije (AIDS) Kombinacija opisana kako slijedi:
Kombinacija spojeva, koji su spoj J i nukleozidni analozi, inhibitor obrnute transkiptaze HIV-a 3TC, i, izborno, nukleozidni inhibitor obrnute transkriptaze odabran između AZT, ddI i ARC-a, ili njihove farmaceutski prihvatljive soli ili esteri.
Jedna preporučena kombinacija uključuje kombinaciju Spoja J, 3TC i AZT, koji se primjenjuju istodobno.
Druga preporučena kombinacija uključuje kombinaciju Spoja J, 3TC i AZT, koji se primjenjuju naizmjenično.
Drugu preporučenu kombinaciju čine Spoj J i nukleozidni inhibitor obrnute transkriptaze HIV-a 3TC, ili njihove farmaceutski prihvatljive soli.
Inhibitor proteaze HIV-a Spoj J sintetiziran je protokolom EP 0 541 168, objavljenom 12. svibnja 1993. Spoj J je N-(2(R)-hidroksi-1(S)-indanil)-2(R)-fenilmetil-4-(S)-hidroksi-5-(1-(4-(3-piridilmetil)-2(S)-N’-(t-butil-karboksamido)-piperazinil))-pentanemid, ili njegove farmaceutski prihvatljive soli.
Struktura nukleozidnog analoga 3TC je
[image]
Sintetizira se postupcima C.K.Chu i sur., J.Org.Chem. 56, 6503 (1991); W.B.Choi i sur. J.Am.Chem.Soc. 113, 9377 (1991); L.H.oung i sur., J. Org.Chem. 57. 5563 (1992); R.F. Schinazi i sur., Antimicrob.Agents Chomother, 36, 672 (1992): P.A.Furman i sur., Antimicrob.Agents Chomother, 36, 2686 (19992), EP0494119 i WO 91/11186.
Farmaceutski prihvatljive soli ovog izuma (u obliku vodotopivih, topivih u ulju ili dispergiranih proizvoda) uključuju uobičajene neotrovne soli ili kvatenarne amonijeve soli koje se dobivaju, na pr., od anorganskih ili organskih kiselina ili lužina.
Primjeri takvih kiselih adicijskih soli uključuju acetat, adipat, alginat, aspartat, benzoat, benzensulfonat, bisulfat, butirat, citrat, kamforat, kamforsulfonat, ciklopentanpropionat, diglukonat, dodecilsulfat, etansulfonat, fumarat, glukoheptanoat, glicerofosfat, hemisulfat, heptanoat, heksanoat, hidroklorid, hidrobromid, hidrojodid, 2-hidroksietansulfonat, laktat, maleat, metansulfonat, 2-naftalensulfonat, nikotinat, oksalat, pamoat, pektinat, persulfat, 3-fenilpropionat, pikrat, pivalat, propionat, sukcinat, tartarat, tiocijanat, tosilat i undekanoat. Alkalične soli uključuju amonijeve soli, soli alkalijskih kovina kao što su natrijeve i kalijeve soli, soli zemnoalkalijskih kovina kao što su kalcijeve i magnezijeve soli, soli s organskim lužinama kao što su soli dicikloheksilamina, N-metil-D-glukamina, kao i soli s aminokiselinama kao što su arginin, lizin i druge. Također, alkalične skupine koje sadrže dušik mogu se kvaternizirati agensima poput nižih alkil halida, kao što su metil, etil, propil i butil klorid, bromidi i jodidi; dialkil sulfata kao što su dimetil, dietil, dibutil idiamil sulfati, dugolančani halidi kao što su decil, lauril, miristil i stearil kloridi, bromidi i jodidi, aralkil halidi kao šio su benzil i pentelil bromidi i drugi.
Druge farmaceutski prihvatljive soli uključuju sulfatne soli etanolata i sulfatne soli.
Farmaceutski prihvatljive soli kombinacije ovog izuma uključuju kombinaciju u kojoj se jedna od komponenti nalazi u obliku farmaceutski prihvatljive soli, ili farmaceutski prihvatljive soli kombiniranih komponenti (to jest, soli kombinacije). U jednom načinu primjene ovog izuma korištena je sulfatna sol kombinacije.
Farmaceutski prihvatljivi esteri ovog izuma odnose se na neotrovne estere, osobito alkilne estere poput metil, etil, propil, izopropil, butil, izobutil ili pentil esteri, između kojih prednost ima metil ester. Unatoč tome, po želji se mogu koristiti i drugi esteri, kao što su fenil-C alkil.
Esterifikacija alkohola, kao što je Spoj J ovog izuma, izvodi se različitim konvencionalnim postupcima, uključujući reakciju alkoholne skupine s odgovarajućim anhidridom, karboksilnom kiselinom ili kiselim kloridom. Ove su reakcije, kao i ostali postupci esterifikacije alkohola, u cijelosti jasne poznavateljima struke.
Reakcija alkohola s odgovarajućim anhidridom izvodi se u prisutnosti acilacijskog katalizatora, kao što je 4-DMAP(4-dimetilaminopiridin, također poznat kao N,N-dimetilaminopiridin), piridin ili 1,8-bis(dimetilamino)naftalen.
Reakcija alkohola s odgovarajućom karboksilnom kiselinom izvodi se u prisutnosti dehidrirajućeg agensa i, izborno, alkilacijskog katalizatora. Sredstvo za dehidraciju, koji služi ubrzavanju reakcije uklanjanjem vode, odabrano je između dicikloheksilkarbodiimida (DCC), 1-(3-dimetilaminopropil)-3-etilkarbodiimida (EDC) ili drugih vodotopivih dehidrirajućih tvari.
Za razliku od opisanog puta, reakcija alkohola s odgovarajućom karboksilnom kiselinom može također završiti esterifikacijom ako se izvodi u prisutnosti anhidrida trifluoroctene kiseline i, izborno, piridina. Slijedeća inačica je reakcija alkohola s odgovarajućom karboksilnom kiselinom u prisutnosti N,N-karbonildiimidazola s piridinom.
Reakcija alkohola s kiselinskim kloridom izvodi se uz acilacijski katalizator poput 4-DMAP ili piridina.
Selektivna esterifikacija Spoja J izvodi se različitim postupcima koji su poznati stručnjacima. Tijekom, jednog postupka, alkohol se najprije esterificira s trikloretil derivatom (na pr., monotrikloretil sukcinatom). Nakon kromatografskog izdvajanja željenog estera, provede se redukcijsko izlučivanje trikloretilne skupine pomoću reakcije s cinkovim prahom u octenoj kiselini. Pored opisanog, mogući postupak selektivne esterifikacije je hidroliza bisestera.
Kombinacija spojeva ovog izuma korisna je za inhibiranje proteaze HIV-a, inhibiranje obrnute transkriptaze, sprečavanje ili liječenje infekcije virusom humane imunodeficijencije (HIV), te u liječenju posljedičnih patoloških stanja kao što je AIDS. Liječenje AIDS-a, sprečavanje ili liječenje infekcije HIV-om obilježeno je time što uključuje, ali nije ograničeno na, liječenje širokog spektra stanja infekcije HIV-om: AIDS-a, ARC-a, bilo simptomatskih, bilo asimptomatskih, kao aktualne ili potencijalne izloženosti HIV-u.
Na primjer, spojevi ovog izuma korisni su u liječenju infekcija HIV-om nakon moguće prethodne izloženosti HIV-u, na pr. transfuzijom krvi, izmjenom tjelesnih tekućina, ugriza, ubodnih incidenata ili izloženosti krvi bolesnika tijekom kirurškog zahvata.
U ove svrhe, kombinacije ovog izuma mogu se primijeniti peroralno, parenteralno (uključujući potkožne injekcije, intravenske, intramuskularne, intrasternalne injekcije kao i primjenu infuzijama), inhaliranjem spreja ili rektalno, u pripravcima koji sadrže uobičajene neotrovne farmaceutski prihvatljive nosače i adjuvanse.
Ovaj izum donosi postupak liječenja kao i farmaceutski pripravak za liječenje infekcije HIV-om i AIDS-a. Liječenje uključuje primjenu na bolesnika, u slučaju potrebe za takvim liječenjem, farmaceutskog pripravka koji sadrži farmaceutski nosač i terapijski učinkovitu količinu svakog spoja u kombinaciji ovog izuma.
Ovi farmaceutski pripravci mogu biti u obliku suspenzija ili tableta za peroralnu primjenu, nazalnog spreja, sterilnih pripravaka za injiciranje, na pr. -sterilnih vodenih ili uljnih suspenzija za injiciranje ili supozitorija.
Prema postupcima ovog izuma, pojedini sastojci kombinacije mogu se primjenjivati istodobno u različito vrijeme tijekom liječenja, ili istodobno, u podijeljenim ili jednostrukim oblicima. Na primjer, u kombinaciji dvaju sastojaka, i to inhibitora proteaze HIV-a, Spoja J, i nukleozidne obrnute transkriptaze HIV-a, 3TC, liječenje 3TC-om može se provoditi prije, nakon ili istodobno s liječenjem Spojem J. Ovaj izum zato treba promatrati tako da obuhvaća sve režime istodobnog liječenja ili liječenja u slijedu, a u tom smislu treba shvatiti i izraz "primjena".
Kada se primjenjuju peroralno kao suspenzija, ovi se pripravci pripravljaju tehnikama koje su dobro poznate u farmaceutskoj struci i mogu sadržavati mikrokristaličnu celulozu za dobivanje mase, alginsku kiselinu ili natrijev alginat kao sredstvo za suspendiranje, metil celulozu kao pospješivač viskoznosti i sladila/sredstva za dobivanje okusa poznata u struci. U obliku tableta za brzo otpuštanje, ovi pripravci sadrže mikrokristaličnu celulozu, dikalcijev fosfat, škrob, magnezijev stearat i laktozu i/ili druge ekscipijense, veziva, produljivače, raspršivače, razrjeđivače i lubrikanse poznate u struci.
Kada se primjenjuju kao nazalni aerosoli ili inhalacije, ovi se pripravci pripravljaju tehnikama dobro poznatim u farmaceutskoj struci i mogu se pripraviti kao slane otopine, korištenjem benzil alkohola u svrhu povećavanja bioraspoloživosti, fluorougljika i/ili drugih sredstava za otapanje ili dispergiranje poznatih u struci.
Otopine ili suspenzije za injiciranje mogu se pripraviti poznatim postupcima, uporabom pogodnih neotrovnih razrjeđivača ili otapala prihvatljivih za parenteralnu primjenu, kao što su manitol, 1,3-butandiol, voda, Ringerova otopina ili izotonična otopina natrijevog klorida, ili pogodna sredstva za raspršivanje, ovlaživanje i suspendiranje poput sterilnih, inertnih, fiksiranih ulja, uključujući sintetičke mono- ili digliceride, te masne kiseline, uključujući oleinsku kiselinu.
Kada se primjenjuju kao rektalno u obliku supozitorija, ovi se pripravci mogu pripraviti miješanjem lijeka s pogodnim nepodražujućim ekscipijensima, kao što su kakao maslac, sintetski esteri glicerida ili polieti1englikoli, koji su pri sobnoj temperaturi u čvrstom stanju, a u rektalnoj šupljini omekšaju i/ili se otope u svrhu otpuštanja lijeka.
Spojevi ovog izuma mogu se primjenjivati na ljude u rasponima doza koji su specifični za svaki pojedini spoj. Spoj J ili njegove farmaceutski prihvatljive soli, primjenjuje se peroralno u rasponu doza između 40 mg i približno 400 mg na dan, podijeljeno u jednu do četiri dnevne doze. Jedan od preporučljivih raspona doza Spoja J je između 300 mg i približno 1200 mg svakih 8 sati. Jedan od preporučljivih raspona doza AZT-a (zidovudina) je između 50 mg i približno 600 mg svakih 8 sati. Jedan od preporučenih raspona doza 3TC-a je između 20 mg i približno 500 mg dva puta dnevno. Unatoč tome, podrazumijeva se da se specifične razine doza kao i učestalost primjene mogu za svakog pojedinog bolesnika mijenjati ovisno o nizu činitelja uključujući aktivnost specifičnog upotrebljenog spoja, njegovu metaboličku postojanost i duljinu djelovanja, dob, tjelesnu težinu, opće zdravstveno stanje, spol, način prehrane, način i vrijeme primjene, brzinu izlučivanja, kombinacije lijekova, važnost pojedinog uvjeta i terapiju koju domaćin prima.
Kombinacija ovog izuma također se može po želji kombinirati s trećim sastojkom protuvirusnog djelovanja, koji je nukleozidni inhibitor obrnute transkriptaze HIV-a. Na primjer, kombinacija ovog izuma može se uspješno primijeniti, u razdoblju prije izlaganja i/ili nakon izlaganja, u kombinaciji s učinkovitim količinama lijekova protiv AIDS-a, i to AZT, ddI ili ddC, koji su poznati poznavateljima struke.
Tablica 1
Protuvirusna sredstva
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AZT je sintetiziran slijedećim postupcima: J.P.Horwitz i sur., J.Org.Chem., 29, 2076 (1964); R.P.Glinski i sur., J.Org.Chem., 38, 4299 (1973); C.K.Chu i sur., Tetrahedron Letters, 29, 5349 (1988). Primjena AZT kao terapijskog sredstva u liječenju AIDS-a opisana je u SAD patentnom zahtjevu broj 4724232.
Spoj ddC sintetiziran je slijedećim postupcima: J.P.Horwitz i sur., J.Org.Chem., 32, 817 (1967); R.Marumoto i M.Honjo, Chem.Pharm.Bull., 22, 128 (1974); T-S.Lin i sur., J.Med.Chem., 30, 440 (1987). Primjena ddC kao terapijskog sredstva u liječenju AIDS-a opisana je u SAD patentnom zahtjevu br. 4879277 i br. 5028595.
Spoj ddI sintetiziran je postupcima iz SAD patentnog zahtjeva br. 5011774; i V.Bhat i sur., Synthetic Commun., 22 (10), 1481-86 (1992). Primjena ddI kao terapijskog sredstva u liječenju AIDS-a opisana je u SAD patentnom zahtjevu br. 5234539.
Preporučene kombinacije služe istodobnom ili izmjeničnom liječenju inhibitorom proteaze HIV-a i nenukleozidnim inhibitorom obrnute transkriptaze HIV-a. Treći sastojak koji se po želji može dodati ovoj kombinaciji je nukleozidni inhibitor obrnute transkiptaze HIV-a, kao što je AZT, ddC ili ddI.
Ove kombinacije mogu imati sinergističke učinke na ograničavanje širenja HIV-a.. Time, ovaj iz u m sadrži trojnu kombinaciju inhibitora proteaze H IV-a Spoja J s nukleozidnim inhibitorom obrnute transkriptaze HIV-a 3TC i nukleozidnim inhibitorom obrnute transkriptaze HIV-a koji je odabran između AZT, ddI i ddC. U ovakvoj trojnoj kombinaciji, liječenje može bili istodobno, izmjenično ili na oba načina.
Primjer 1
Protokol kombinacijske terapije Spojem J, AZT-om i 3TC-om
U jednom uzorku, liječeno je približno 90 odraslih osoba oba spola, u dobi od 18 ili više godina, koje su seropozitivne na HIV-1. Bolesnici su mogli biti prethodno liječeni zidovudinom tijekom približno šest mjeseci ili više. Broj CD4 stanica iznosio je između 50 i 400 stanica/mm3, a vrijednost virusne RNA u serumu bila je jednaka ili veća od 20000 kopija/mL. Osnovna je zadaća protokola primjena 800 mg Spoja J, podijeljeno na obroke svakih 8 sati u kombinaciji s 200 mg zidovudina podijeljeno na obroke svakih 8 sati i 150 mg 3TC-a dvaput dnevno.
Doze/načini doziranja, put i režim doziranja
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Primjer 2
Protokol kombinacijske terapije spojem J i 3TC-om
U jednom uzorku, liječeno je približno 90 odraslih osoba oba spola, u dobi od 18 ili više godina, koje su seropozitivne na HIV-1. Bolesnici su mogli biti prethodno liječeni zidovudinom tijekom približno šest mjeseci ili više. Broj CD4 stanica iznosio je između 50 i 400 stanica/mm3, a vrijednost virusne RNA u serumu bila je jednaka ili veća od 20000 kopija/mL. Osnovna je zadaća protokola primjena 800 mg Spoja J, podijeljeno na obroke svakih 8 sati u kombinaciji sa 150 mg 3TC-a dvaput dnevno.
Doze/načini doziranja, put i režim doziranja
[image]
Iako su u gore navedenoj specifikaciji izložena načela ovog izuma, s primjerima koji su izloženi u svrhu pojašnjenja, podrazumijeva se da u praksi ovaj izum obuhvaća sve uobičajene inačice, prepravljanja i izmjene koje se nalaze unutar slijedećih patentnih zahtjeva i njihovih ekvivalenata.
Claims (13)
1. Kombinacija spojeva, naznačena time, što ju čine Spoj J i nukleozidni analog obrnute transkriptaze HIV-a 3TC i, izborno, nukleozidni inhibitor obrnute transkriptaze HIV-a koji je odabran između AZT, ddI i ddC, ili njihove farmaceutski prihvatljive soli ili esteri.
2. Kombinacija iz Zahtjeva 1, naznačena time, što ju čine Spoj J i 3TC.
3. Kombinacija iz Zahtjeva 1, naznačen time, što ju čine Spoj J, 3TC i AZT.
4. Kombinacija iz Zahtjeva 1, naznačena time, što ju čine 3TC i ddI.
5. Kombinacija iz Zahtjeva 1, naznačena time, što ju čine Spoj J, 3TC i ddC.
6. Kombinacija Spoja J, 3TC i AZT, naznačena time, što se primjenjuje istodobno.
7. Kombinacija Spoja J, 3TC i AZT, naznačena time, što se primjenjuju izmjenično.
8. Postupak inhibiranja proteaze HIV-a, naznačen time, što uključuje primjenu na pogodnog sisavca učinkovite količine kombinacije iz Zahtjeva 1 u slučaju potrebe za takvim liječenjem.
9. Postupak inhibiranja obrnute transkriptaze HIV-a, naznačen time, što uključuje primjenu na pogodnog sisavca učinkovite količine kombinacije iz Zahtjeva l u slučaju potrebe za takvim liječenjem.
10. Postupak sprečavanja infekcije HIV-om ili liječenja infekcije HIV-om, ili liječenja AIDS-a ili ARC-a, naznačen time, što uključuje primjenu na pogodnog sisavca učinkovite količine kombinacije iz Zahtjeva 1 u slučaju potrebe za takvim liječenjem.
11. Farmaceutski pripravak koristan za inhibiranje proteaze HIV-a, naznačen time, što sadrži učinkovitu količinu kombinacije iz Zahtjeva 1 i farmaceutski prihvatljiv nosač.
12. Farmaceutski pripravak koristan za inhibiranje obrnute transkriptaze HIV-a, naznačen time, šio sadrži učinkovitu količinu kombinacije iz Zahtjeva 1 i farmaceutski prihvatljiv nosač.
13. Farmaceutski pripravak koristan za sprečavanje ili liječenje infekcije HIV -om, ili za liječenje AIDS - a ili ARC-a, naznačen time, što sadrži učinkovitu količina kombinacije iz Zahtjeva 1 i farmaceutski prihvatljiv nosač.
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| US08/382,113 US6689761B1 (en) | 1995-02-01 | 1995-02-01 | Combination therapy for HIV infection |
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| HRP960045A2 true HRP960045A2 (en) | 1997-10-31 |
| HRP960045B1 HRP960045B1 (en) | 2004-06-30 |
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| US (1) | US6689761B1 (hr) |
| EP (1) | EP0806957B1 (hr) |
| JP (1) | JPH10513186A (hr) |
| KR (1) | KR19980701856A (hr) |
| CN (1) | CN1160081C (hr) |
| AR (1) | AR002957A1 (hr) |
| AT (1) | ATE243519T1 (hr) |
| AU (1) | AU711176B2 (hr) |
| BR (1) | BR9607714A (hr) |
| CA (1) | CA2211973A1 (hr) |
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| EE (1) | EE03514B1 (hr) |
| ES (1) | ES2200052T3 (hr) |
| FI (1) | FI973184A (hr) |
| HK (1) | HK1004659A1 (hr) |
| HR (1) | HRP960045B1 (hr) |
| HU (1) | HUP9800810A3 (hr) |
| IL (1) | IL116925A (hr) |
| IS (1) | IS1970B (hr) |
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| EP0942747A1 (en) * | 1996-08-26 | 1999-09-22 | Chiron Corporation | Postinfection human immunodeficiency virus (hiv) vaccination therapy |
| WO1999047146A1 (en) * | 1998-03-17 | 1999-09-23 | Julianna Lisziwiewicz | Anti-hiv combination comprising hydroxyurea, ddi, and a protease inhibitor |
| CA2374198A1 (en) * | 1998-05-29 | 1999-12-02 | Maki Arai | Combination therapy for treatment of fiv infection |
| US6875773B1 (en) | 1998-05-29 | 2005-04-05 | Ben M. Dunn | Combination therapy for treatment of FIV infection |
| WO2000039304A2 (en) | 1998-12-31 | 2000-07-06 | Chiron Corporation | Polynucleotides encoding antigenic hiv type c polypeptides, polypeptides and uses thereof |
| AU2002320314A1 (en) | 2001-07-05 | 2003-01-21 | Chiron, Corporation | Polynucleotides encoding antigenic hiv type c polypeptides, polypeptides and uses thereof |
| CA2583195A1 (en) * | 2004-11-19 | 2006-05-26 | Boehringer Ingelheim International Gmbh | Method for treating hiv infection through co-administration of tipranavir and reverset |
| US7745455B2 (en) | 2005-07-27 | 2010-06-29 | Emil Toma | Zalcitabine (ddC) boosted lamivudine (3TC) compositions for antiretroviral therapy |
| EP3565554A4 (en) * | 2017-01-04 | 2020-08-19 | Oyagen, Inc. | COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS |
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| US4724232A (en) * | 1985-03-16 | 1988-02-09 | Burroughs Wellcome Co. | Treatment of human viral infections |
| US5254539A (en) * | 1985-08-26 | 1993-10-19 | U.S. Government, Dept. Of Health And Human Services, C/O National Institutes Of Health | Method of treating HIV with 2',3'-dideoxyinosine |
| US5028595A (en) * | 1987-09-18 | 1991-07-02 | Hoffmann-La Roche Inc. | Method for preventing AIDS in a subject or treating a subject infected with the AIDS virus |
| US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
| IL100502A (en) | 1991-01-03 | 1995-12-08 | Iaf Biochem Int | PHARMACEUTICAL PREPARATIONS CONTAINING CIS-4-AMINO-1-) 2-HYDROXIMETHIL-1,3-OXETYOLEN-5-IL (- |
| US5413999A (en) | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
| WO1994022480A1 (en) | 1993-03-31 | 1994-10-13 | Merck & Co., Inc. | Hiv protease inhibitors in pharmaceutical combinations for the treatment of aids |
| IL114208A0 (en) | 1994-06-27 | 1995-10-31 | Merck & Co Inc | Combinations of compounds pharmaceutical compositions containing them and their use as hiv protease inhibitors |
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1995
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- 1996-01-29 CA CA002211973A patent/CA2211973A1/en not_active Abandoned
- 1996-01-29 AU AU47748/96A patent/AU711176B2/en not_active Ceased
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- 1996-02-01 CO CO96004316A patent/CO4700430A1/es unknown
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- 1996-03-12 SA SA96160669A patent/SA96160669B1/ar unknown
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