HRP20020342A2 - Use of dipyridamole or mopidamol in the manufacture of a medicament for the teatment and prevention of fibrin-dependent microcirculation disorders - Google Patents
Use of dipyridamole or mopidamol in the manufacture of a medicament for the teatment and prevention of fibrin-dependent microcirculation disorders Download PDFInfo
- Publication number
- HRP20020342A2 HRP20020342A2 HR20020342A HRP20020342A HRP20020342A2 HR P20020342 A2 HRP20020342 A2 HR P20020342A2 HR 20020342 A HR20020342 A HR 20020342A HR P20020342 A HRP20020342 A HR P20020342A HR P20020342 A2 HRP20020342 A2 HR P20020342A2
- Authority
- HR
- Croatia
- Prior art keywords
- dipyridamole
- microcirculation
- disease
- pyrimido
- pyrimidine
- Prior art date
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- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 title claims description 62
- 229960002768 dipyridamole Drugs 0.000 title claims description 61
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- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 title claims description 23
- 229950003499 fibrin Drugs 0.000 title claims description 23
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- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 title description 3
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- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical compound N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 claims description 14
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Description
Područje izuma
Ovaj izuma se odnosni na metodu liječenja mikro-cirkulacijskih poremećaja ovisnih o fibrinu upotrebom dipiridamola ili mopidamola kao aktivne tvari, koja osigurava trajno poboljšanje mikrocirkulacije tijekom liječenja, i na upotrebu dipiridamola ili mopidamola za proizvodnju odgovarajućeg farmaceutskog pripravka.
Pozadina izuma
Dipiridamol, (2,6-bis(dietanolamino)-4,8-dipiperidino-pirimido[5,4-d]pirimidin), usko srodni supstitutirani pirimido-pirimidini i njihova priprava opisani su npr. u U.S. patentu 3,031,450. Daljnji srodni supstituirani pirimido-pirimidini i njihova priprava opisani su npr. u GB 1,051,218, između ostalog i spoj mopidamol (2,6-bis-(dietanolamino)-4-piperidinopirimido[5,4-d]pirimidin). Dipiridamol je uveden kao koronarni vazodilator ranih šezdesetih. Također je poznato da ima svojstva inhibitora agregacije trombocita zbog inhibicije uzimanja adenozina. Nakon toga se je na modelu proučavanja arterijske cirkulacije u mozgu zečeva pokazalo da dipiridamol reducira stvaranje tromba. Ta istraživanja su dovela do njegove upotrebe kao antitromboznog sredstva; i je ubrzo postao terapija izbora za takove aplikacije kao što je prevencija udara kapi, održavanje raširenosti koronarnog premoštenja i zamjene ventila, kao i za liječenje prije koronarne angioplastije.
Osim toga, Europska studija 2 prevencije udara kapi (European Stroke Prevention Study 2 (ESPS-2; J Neurol Sci. 1996; 143: 1-13; Neurology 1998; 51: 17-19)) je potvrdila da je liječenje samo s dipiridamolom bilo učinkovito kao niska doza aspirina u smanjenju opasnosti od udara kapi, a kombinirana terapija s dipiridamolom i aspirinom bila više nego dvostruko učinkovitija od samog aspirina.
Čini se da dipiridamol inhibira trombozu višestrukim mehanizmom. Rane studije su pokazale da on inhibira vezanje adenozina, za kojeg je nađeno da je jaki endogeni anti-trombozni spoj. Također se je pokazalo da dipiridamol jako inhibira cikličku AMP fosfodiesterazu, i time povisuje intracelularnu c-AMP.
Pomoću laboratorijskih modela koji odražavaju složenu fiziologiju krvnih žila može se pokazati da vaskulatura nije samo pasivna cijev, već da ona intenzivno stupa u interakcije s krvi preko zamršenog sistema provjeravanja i balansiranja sa ciljem da zaštiti svoju cjelovitost nakon vaskularne nezgode. Zbog toga endotel proizvodi prostaciklin, jaki inhibitor agregacije. Normalni endotel nije trombogen i on sprečava povezivanje krvnih pločica. Razni stimulanti ubrzavaju oslobađanje faktora otpuštanja deriviranog iz endotela (e. endotelium-derived relaxing factor (EDRF)) koji inhibira adheziju krvnih pločica i agregaciju. Istovremeno, pokazalo se je da je intracelularni porast cGMP-a odgovoran za opuštanje stanica glatkih mišića nakon aplikacije nitro spojeva. Tako, dakle, endotel može inhibirati stvaranje tromba pomoću dva odvojena mehanizma, jednog koji je posredovan s prostaciklinom i c-AMP, i drugog pomoću EDRF i c-GMP. Čini se da dipiridamol pojačava ta obadva antitrombozna mehanizma stijenke krvne žile, pored njegovog učinka štednje adenozina. On stimulira proizvodnju prostaciklina povećanjem intracelularnih količina cAMP-a, i on povećava jačinu sistema antitromboznog dušičastog oksida povisujući cGMP.
Dipiridamol ima također i svojstva antioksidanta (Free Radić. Biol . Med. 1995; 18: 239-247) koja mogu doprinijeti njegovom antitromboznom učinku. Receptor za čišćenje (e. scavenger receptor) na makrofagima prepoznaje lipoproteine niske gustoće kad su oni oksidirani, što se smatra nužnim korakom u razvoju ateroskleroze (Ann. Rev. Med. 1992; 43: 219-25).
Nađeno je da inhibicija stvaranja slobodnih radikala pomoću dipiridamola inhibira fibrinogenezu u eksperimentalnoj fibrozi jetre (Hepatology 1996; 24; 855-864) i da potiskuje kisikove radikale i proteinuriju u eksperimentalnim životinjama s amino-nukleozidnom nefropatijom (Eur. J. Clin. Invest. 1998; 28; 877-883; Renal Physiol. 1984; 7: 218-226). Inhibicija peroksidacije lipida je također opažena u humanom ne-neoplastičnom plućnom tkivu (Gen. Pharmacol. 1996; 27: 855-859).
Za mopidamol se zna da ima antitrombozna i k tome još i antimetastazna svojstva.
Kratki opis izuma
Iznenađujuće je pronađeno da dipiridamol i mopidamol pokazuju zaštitni učinak na stijenkama krvnih žila čime jako utječu na interakciju stijenke krvne žile s fibrinskom stazom sistema koagulacije što ima za posljedicu bitno smanjenje akumulacije fibrina nakon stimulacije stvaranja ugruška.
Poznato je da vaskularne ozljede ubrzavaju akumulaciju fibrina jer kompleks protrombinaze postaje značajno jači kad se taloži na fosfolipide stanične membrane negativnog naboja. Stabilizacijom stanične membrane, na vanjskoj staničnoj membrani se izlažu fosfadidilserini s negativnim nabojem, nudeći manje mogućnosti za vezanje kompleksa protrombinaze na fosfolipide, i time se sprečava da kompleks protrombinaze sudjeluje svojim ukupnim udjelom na pretvorbi protrombina u trombin koji je odgovoran za pretvorbu fibrinogena u fibrin.
Srašćivanje trombocita i akumulacija fibrina su osnovne staze uključene u stvaranje ugruška. Dokazano je da se vremenski tijek tih dvaju staza bitno razlikuje (Thromb. Haemost. 1993; 69 (Abstr.): 569) što potvrđuje da ta dva mehanizma nisu povezana tako čvrsto kako se je to pretpostavljalo. Dok je djelovanje dipiridamola i mopidamola kao inhibitora agregacije trombocita dobro poznato, sada je pronađeno da su ta sredstva još k tome i inhibitori akumulcije fibrina posredovane s njihovom sposobnošću da stabiliziraju stanične membrane stijenki krvnih žila. Taj učinak je posebno važan u malim krvnim žilama ili kapilarama gdje je omjer površine stijenke krvne žile prema volumenu krvi visok i pruža nov pristup liječenju i prevenciji mikrocirkulacijijskih poremećaja ovisnih o fibrinu. Zbog toga dipiridamol i mopidamol imaju terapeutsku mogićnost u raznim bolestima koje uključuju progresivnu disfunkciju krvnih žila srednje i male veličine. Smatralo se je općenito da je poznato vazodilatacijsko djelovanje dipiridamola mnogo važnije u većim krvnim žilama i u pogledu kratkotrajnog liječenja ili prevencije akutnih stanja. Upotrebom dipiridamola kao udarnog ispitnog sredstva poznato je da kratkotrajnom infuzijom visoke doze dipiridamola vaskularna samoregulacija izaostaje što pokazuje nesrazmjernu perfuziju. To se koristi za razlikovanje manjeg porasta protoka krvi u područjima post-stenta u usporedbi s većim porastom u zdravim segmentima cirkulacije kod nuklearnog slikanja ili ehokardiografije. U slučaju dugotrajnog oralnog liječenja količine dipiridamola u plazmi kao i odgovarajuće količine adenozina rastu tijekom perioda od nekoliko sati što samoregulatorskim sistemima omogućuje kompenziranje, čime pod uvjetima "udarnog ispitivanja" količine dipiridamola u plazmi kao i količine adenozina dosižu njihove vršne vrijednosti za par minuta. Nađeno je da liječenje prema predložnom izumu osigurava trajni učinak na malim kapilarnim žilama i time trajno poboljšanje mikrocirkulacije.
Otkriće da dipiridamol i mopidamol imaju značajne inhibitorske učinke na akumulaciju fibrina preko stijenki krvnih žila i stabilizacijski učinak na stanične membrane nudi se razumljivo također za kombinirano liječenje zajedno s drugim antitromboznim sredstvima kao što su inhibitori agregacije trombocita, npr. acetilsalicalna kiselina (ASA), klopidogrel ili tiklopidin ili njihove farmaceutski prihvatljive soli, antagonisti fibrinogen receptora (abciksimab, RDGS-peptidi, sintetički i.v. ili oralni fibrinogen antagonisti, npr. fradafiban, lefradafiban ili njihove farmaceutski prihvatljive soli), heparin i heparinoidi ili antitrombini, ili za kombinirano liječenje upotrebom dodatnih kardiovaskularnih terapija kao to je liječenje s ACE inhibitorima, angiotenzin II antagonistima, Ca-antagonistima ili sa sredstvima za sniženje lipida kao što su statini.
ASA inhibira agregaciju izravnim učincima na trombocite, pobliže ireverzibilnim acetiliranjem ciklo-oksigenaze trombocita, inhibirajući time proizvodnju tromboksana, koji je jako trombozan. Međutim, u visokim dozama, aspirin prodire u endotelne stanice (N. Eng. J. Med. 1984; 311: 1206-1211), gdje on prekida proizvodnju prostaciklina, jakog prirodnog inhibitora agregacije trombocita i sporednog proizvoda "arahidonske kaskade" (N. Engl. J. Med. 1979; 300: 1142-1147). Ta opažanja su dovela do ideje antitrombocitne terapije niskih doza s ASA da se maksimira inhibiciju tromboksana uz minimalan gubitak prostaciklina (Lancet 1981; 1: 969-971). U kombinaciji s dipiridamolom ili mopidamolom u skladu s izumom također se daje prednost ideji niske doze ASA.
Gledano s jednog aspekta, predloženim izumom data je metoda za liječenje tijela humanog ili ne-humanog bića, ponajprije tijela sisavca, za liječenje ili prevenciju mikrocirkulacijskih poremećaja ovisnih o fibrinu ili bolesnih stanja u koja su uključeni takovi poremećaji mikrocirkulacije, pri čemu spomenuta metoda uključuje davanje spomenutom tijelu učinkovite količine farmaceutskog pripravka koji sadrži pirimido-pirimidin odabran između dipiridamola, mopidamola i njihovih farmaceutski prihvatljivih soli, pri čemu se prednost daje dipiridamolu, prema potrebi u kombinaciji s jednim ili više drugih antitromboznih sredstava.
Gledano s drugačijeg aspekta, predloženi izum osigurava upotrebu pirimido-pirimidina odabranog između dipiridamola, mopidamola i njihovih farmaceutski prihvatljivih solim pri čemu se prednost daje dipiridamolu, prema potrebi u kombinaciji s jednim ili više drugih antitromboznih sredstava za proizvodnju farmaceutskog pripravka za liječenje tijela humanog ili ne-humanog bića, ponajprije tijela sisavca, za liječenje ili prevenciju mikrocirkulacijskih poremećaja ovisnih o fibrinu ili bolesnih stanja u koja su uključeni takovi poremećaji mikrocirkulacije.
Opis izuma u pojedinostima
Izumom je dat novi pristup liječenju i prevenciji mikrocirkulacijskih poremećaja povezanih s progresivnom disfunkcijom krvnih žila srednje i male veličine koji uključuje davanje osobi, kojoj je potrebno takovo liječenje, učinkovite količine farmaceutskog pripravka koji sadrži pirimido-pirimidin odabran između dipiridamola, mopidamola i njihovih farmaceutski prihvatljivih soli.
Pod mikrocirkulacijskim poremećajima koji su ovisni o fibrinu misli se na takove poremećaje u kojima je taloženje fibrina uključeno u patogenezu ili progresiju disfunkcije krvnih žila srednje ili male veličine što dovodi do raznih kliničkih slika. Poznato je da metaboličke bolesti kao dijabetes melitus uzrokuju spomenute mikrocirkulacijske poremećaje, međutim, upalne reakcije mogu također uzrokovati mikrocirkulacijske poremećaje zbog lokalnog oslobađanja fibrinogena iz tkiva na mjestu upale. Osim toga, misli se da mikrocirkulacijske poremećaje također mogu uzrokovati i autoimunosne reakcije.
Podrazumijeva se da su u indikacije "mikrocirkulacijskih poremećaja ovisnih o fibrinu" bez ograničenja uključeni
- poremećaj i mikrocirkulacije uzrokovani metaboličkim bolestima u koje su uključena vaskularna oštećenja, kao što je diabetska angiopatija, posebno dijabetska mikroangiopatija, npr. dijabetska gangrena, dijabetska retinopatija, dijabetska neuropatija ili ulcus cruris,
- poremećaji mikrocirkulacije uzrokovani upalnim reakcijama, kao što je Krohnova bolest,
- poremećaj i mikrocirkulacije uzrokovani autoimunosnim bolestima, kao što je autoimunosni, kronično aktivan hepatitis (idiopatski hepatitis), primarna bilijarna ciroza ili (povezana s autoimunitetom) multipla skleroza,
- periferni poremećaji mikrocirkulacije, kao što je Raynaudova bolest, tinitus ili iznenadan gubitak sluha,
- poremećaji mikrocirkulacije povezani s povećanom diobom stanica, kao što su tumorske bolesti ili trombozno-trombo-citopenična purpura (TTP),
- i, kao daljnje indikacije, nefroskleroza, prerenalna hipertenzija, hemolitizno-uremijski sindrom (HUS), arterijska hipertenzija, vaskularna demencija, Alzheimerova bolest, Sudeckova bolest, središnja venska tromboza oka, ishemijska optička neuropatija, s homocistinom inducirana vaskulopatija, ishemijske ili koronarne srčane bolesti, prevencija miokardijalnog infarkta ili ponovnog infarkta i liječenje ili prevencija ateroskleroze.
Indikacija "mikrocirkulacijskih poremećaja ovisnih o fibrinu" također uključuje odgovarajuće miokardijalne poremećaje.
Tako, dakle, predloženi izum osigurava metodu za poboljšanje dotoka krvi miokardija kod osobe kojoj je potrebno takovo liječenje, na primjer kod osobe koja pati od ishemijske ili koronarne srčane bolest, kao i metodu za prevenciju miokardijalnog infarkta ili ponovnog infarkta.
Osim toga, predloženi izum također daje metodu za liječenje ili prevenciju ateroskleroze jer davanje dipiridamola ili mopidamola potpomaže ili pomaže poboljšanju ili ponovnom uspostavljanju mikrocirkulacije dotokom krvi u žile.
Kao što je već ranije spomenuto, dipiridamol, mopidamol ili njihove farmaceutski prihvatljive soli mogu se upotrijebiti sami u monopripravku ili u kombinaciji s drugim antitromboznim sredstvima za liječenje mikro-cirkulacijskih poremećaja ovisnih o fibrinu.
Korisno je održavati u plazmi količinu dipiridamola ili mopidamola od pribl. 0,2 do 5 μmol/l, ponajprije od pribl. 0,4 do 5 μmol/l, naročito od pribl. 0,5 do 2 μmol/l ili posebno od pribl. 0,8 do 1,5 μmol/l. To se može postići uzimanjem bilo koje oralne, odmah gotove ili parenteralne formulacije ili formulacije za usporeno oslobađanje, koje se nalaze na tržištu, pri čemu se prednost daje formulacijama za usporeno oslobađanje, na primjer onoj koja se može dobiti pod trgovačkim nazivom Persantin®, ili, za kombiniranu terapiju s niskom dozom ASA, upotrebom onih formulacija koje se mogu dobiti pod trgovačkim nazivom Asasantin® ili Aggrenox®. Formulacije dipiridamola za usporeno oslobađanje su također opisane u EP-A-0032562, gotove formulacije su opisane u EP-A-0068191 i kombinacije ASA s dipiridamolom su opisane u EP-A-0257344 što je ovdje uvršteno kao literatura. U slučaju mopidamola također se mogu upotrijebiti oralne, odmah gotove ili parenteralne formulacije ili formulacije za usporeno oslobađanje, npr. one koje su opisane u GB 1,051,218 ili EP-A-0, 108, 898 što je ovdje uvršteno kao literatura, a pri čemu se prednost daje formulacijama za usporeno oslobađanje.
Dipiridamol ili mopidamol se može dati oralno dnevnom dozom od 25 do 450 mg, ponajprije 50 do 240 mg, ponajbolje 75 do 200 mg. Za dugotrajno liječenje povoljno ga je dati u ponavljajućim dozama, kao što je doza od 25 mg dipiridamola, u formulaciji za usporeno oslobađanje ili u bilo kojoj drugoj formulaciji za trenutno oslobađanje tri ili četiri puta dnevno. Za parenteralnu aplikaciju, dipiridamol se može dati s doziranjem od 0,5 do 5 mg/kg tjelesne težine, ponajprije 1 do 3,5 mg/kg tjelesne težine tijekom 24 sata kao polagana i.v. infuzija (ne brže od 0,2 mg/min).
Dipiridamol ili mopidamol u kombinaciji s niskom dozom ASA mogu se dati oralno dnevnim doziranjem od 10 do 30 mg ASA zajedno s 50 do 300 mg dipiridamola ili mopidamola, ponajprije 80 do 240 mg dipiridamola ili mopidamola, na primjer u masenom omjeru između 1 do 5 i 1 do 12, ponajbolje u masenom omjeru od l do 8, na primjer 25 mg ASA zajedno s 200 mg dipiridamola ili mopidamola.
Drugi antitrombozni spojevi se mogu dati količinom koja iznosi od 0,1 do 10 puta, ponajprije od 0,3 do 5,0 puta, ponajbolje od 0,3 do 2,0 puta od klinički propisane doze (npr. Rote Liste® 1999; fradafiban, lefradafiban: EP-A-0483667), zajedno s dnevnom dozom od 25 do 450 mg, ponajprije od 50 do 240 mg, ponajbolje od 75 do 200 mg dipiridamola ili mopidamola.
Za kombinirano liječenje upotrebom dipiridamola ili mopidamola zajedno s ACE inhibitorima može biti prikladan bilo koji u struci poznat ACE inhibitor, npr. benazepril, kaptopril, ceronapril, enalapril, fosinopril, imidapril, lisinopril, moeksipril, kvinapril, ramipril, trandolapril ili perindopril, primjenom u struci poznatog doziranja, kako je propisano na primjer u Rote Liste® 1999, izdanje Cantor Verlag Aulendorf.
Za kombinirano liječenje upotrebom dipiridamola ili mopidamola zajedno s angiotenzin II antagonistima može biti prikladan bilo koji u struci poznat angiotenzin II antagonist, npr. sartani kao kandesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, olmesartan ili tasosartan, primjenom u struci poznatog doziranja, kako je propisano npr. u Rote Liste® 1999, izdanje Cantor Verlag Aulendorf.
Za kombinirano liječenje upotrebom dipiridamola ili mopidamola zajedno s Ca-antagonistima može biti prikladan bilo koji u struci poznat Ca-antagonist, npr. nifedipin, nitrendipin, nisoldipin, nilvadipin, isradipin, felodipin ili lacidipin, primjenom u struci poznatog doziranja kako je propisano na primjer u Rote Liste® 1999, izdanje Cantor Verlag Aulendorf.
Za kombinirano liječenje upotrebom dipiridamola ili mopidainola zajedno sa statinima može biti prikladan bilo koji u struci poznati statin, npr. lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin ili cerivastatin, primjenom u struci poznatog doziranja kako je popisano na primjer u Rote Liste® 1999, izdanje Cantor Verlag Aulendorf.
Treba napomenuti da takovi mikrocirkulacijski poremećaji povezani s povećanom diobom stanice, kako je ranije spomenuto, posebno ubrzavaju akumulaciju fibrina zbog slobodnih površina staničnih membrana koje mogu aktivirati kompleks protrombinaze. Ti mikrocirkulacijski poremećaji, na primjer tumorske bolesti ili trombozna-trombocitopenična purpura, se liječe ponaprije primjenom visokih doza dipiridamola ili mopidamola. To znači da se količine dipiridamola ili mopidamola u plazmi od pribl. 0,2 do 50 μmol/l, ponajprije od pribl. 0,5 do 20 μmol/l, posebno povoljno od pribl. 0,5 do 10 μmol/l moraju održavati pomoću polagane i.v. infuzije. Za oralno liječenje tih indikacija dipiridamol ili mopidamol se moraju davati u dnevnom doziranju od pribl. 150 do 1000 mg, ponajprije od 200 do 800 mg, ponajbolje od 200 do 600 mg.
Mikrocirkulacijski poremećaji povezani s povećanom diobom stanica mogu se također liječiti s kombinacijom dipiridamola ili mopidamola s niskom dozom ASA primjenom gore spomenutih visokih doza dipiridamola ili mopidamola, zajedno s oralnim dnevnim doziranjem od pribl. 10 do 30 mg ASA, ponajprije od pribl. 25 mg ASA.
Za proučavanje inhibicije akumulacije fibrina pomoću dipiridamola proveden je slijedeći pokus:
Proučavanje pomoću radioaktivno obilježenih trombocita i fibrinogena in vivo
Učinci dipiridamola i heparina su istraženi upotrebom trombocita radioaktivno obilježenih s 99Tc i fibrinogena obiježenog sa 123J. Metoda je opisana u Nuclear Instruments and Methods in Physics Research A. 1994, 353: 448-452. Detektor radijacije osjetljiv prema energiji krutog stanja stavljen je tako da je okruživao svaku karotidnu arteriju zečeva. Nakon izazivanja ozljede angioplastijom balona, srašćivanje trombocita i fibrinogena praćeno je četiri sata. Nađeno je da se srašćivanje trombocita i fibrinogena dešava u različito vrijeme. Srašćivanje nije dokazano u radioaktivno obilježenim trombocitima ubrizganim 30 minuta nakon ozljede; očigledno je mjesto angioplastije bilo pasivirano ljepljenjem endogenih trombocita. Suprotno tome, srašćivanje fibrinogena nije doseglo razinu opaženu u kontrolnim ili liječenim životinjama čak niti nakon četiri sata, što pokazuje da drugačiji poticaj ili ciljevi mogu regulirati fibrinogen u raznim trenucima nakon ozljede (slika 1). Liječenje s heparinom smanjuje akumulaciju kako trombocita tako i fibrinogena. Liječenje s dipiridamolom također uzrokuje smanjenje agregacije trombocita, koja je bila slična onoj koja je opažena s heparinom; međutim, smanjenje srašćivanja fibrinogena je bilo daleko veće s dipiridamolom nego s heparinom (slika 2).
Opis slika
Slika 1: Istovremena detekcija trombocita obilježenih s 99Tc i fibrinogena obilježenog sa 123J u razmaku od l minute nakon angioplastije zajedničke karotidne arterije zečeva. Kontrolna (nije liječena) skupina (N=6) pokazala je nakon ozljede brzi porast trombocita i postupno stvaranje fibrinogena. Liječenje s heparinom (100U/kg bolus i zatim s 25U/kg/h infuzijom) pokazalo je smanjenje srašćivanja trombocita kao i fibrinogena. Mjerenja u slučaju bez ozljede pokazuju konstantnu radioaktivnost.
Slika 2: Taloženje radioaktivno obilježenih trombocita (99Tc) i fibrinogena (123J) na mjestu angioplastije nakon liječenja s dipiridamolom (0,25 mg/kg i zatim s 0,45 mg/kg/sat). Taloženje trombocita je smanjeno, dok je srašćivanje fibrinogena gotovo u cijelosti blokirano tijekom prva četiri sata nakon angioplastije.
Claims (12)
1. Postupak liječenja tijela humanog ili ne-humanog bića za liječenje ili prevenciju mikrocirkulacijskih poremećaja ovisnih o fibrinu ili bolesnih stanja u koja su uključeni takovi poremećaji mikrocirkulacije, naznačen time, da se spomentom tijelu daje učinkovitu količinu farmaceutskog pripravka koji sadrži pirimido-pirimidin odabran između dipiridamola, mopidamola i njihovih farmaceutski prihvatljivih soli, prema potrebi u kombinaciji s jednim više drugih antitromboznih sredstava ili prema potrebi u kombinaciji s ACE inhibitorom, angiotenzin II antagonistom, Ca-antagonistom ili sredstvom za sniženje lipida.
2. Postupak prema zahtjevu 1, naznačen time, da pirimido-pirimidin je dipiridamol.
3. Postupak prema zahtjevu 1, naznačen time, da je poremećaj mikrocirkulacija ovisan o fibrinu odabran iz skupine koju čine
poremećaj i mikrocirkulacij e uzrokovani metaboličkim bolestima u koje su uključena vaskularna oštećenja, kao što je diabetska angiopatija, posebno dijabetska mikroangiopatija, npr. dijabetska gangrena, dijabetska retinopatija, dijabetska neuropatija ili ulcus cruris,
poremećaji mikrocirkulacije uzrokovani upalnim reakcijama, kao što je Krohnova bolest,
poremećaj i mikrocirkulacij e uzrokovani autoimunosnim bolestima,
kao što je autoimunosni, kronično aktivan hepatitis (idiopatski hepatitis), primarna bilijarna ciroza ili
(povezana s autoimunitetom) multipla skleroza,
periferni poremećaji mikrocirkulacije,
kao što je Raynaudova bolest, tinitus ili iznenadan gubitak sluha,
poremećaji mikrocirkulacije povezani s povećanom diobom stanica,
kao što su tumorske bolesti ili trombozno-trombo-citopenična purpura (TTP), i, kao daljnje indikacije,
nefroskleroza,
prerenalna hipertenzija,
hemolitizno-uremijski sindrom (HUS),
arterijska hipertenzija,
vaskularna demencija,
Alzheimerova bolest,
Sudeckova bolest,
središnja venska tromboza oka,
ishemijska optička neuropatija,
s homocistinom inducirana vaskulopatija,
ishemijske ili koronarne srčane bolesti,
prevencija miokardijalnog infarkta ili ponovnog infarkta i
liječenje ili prevencija ateroskleroze.
4. Postupak prema zahtjevu 1, naznačen time, da se u plazmi održava od pribl. 0,2 do 5 μmol/l pirimido-pirimidina.
5. Postupak prema zahtjevu 1, naznačen time, da se pirimido-pirimidin daje pomoću oralne, odmah gotove, parenteralne formulacije ili formulacije za usporedno oslobađanje.
6. Postupak prema zahtjevu 1, naznačen time, da se pirimido-pirimidin daje oralno dnevnim doziranjem od 25 do 450 mg ili parenteralnim doziranjem od 0,5 do 5 mg/kg tjelesne težine tijekom 24 sata.
7. Postupak prema zahtjevu 1, naznačen time, da farmaceutski pripravak sadrži pirimido-pirimidin u kombinaciji s acetilsalicilnom kiselinom (ASA) kao drugim antitromboznim sredstvom, i daje se oralno dnevnim doziranjem od 10 do 30 mg ASA zajedno s 50 do 300 mg pirimido-pirimidina.
8. Postupak prema zahtjevu 3, naznačen time, da se za liječenje poremećaja mikrocirkulacije povezanog s povećanom diobom stanica količinu dipiridamola ili mopidamola u plazmi održava pri pribl. 0,2 do 50 μmol/l.
9. Postupak prema zahtjevu 8, naznačen time, da se dodatno daje oralno dnevno doziranje od pribl. 10 do 30 mg ASA.
10. Upotreba pirimido-pirimidina odabranog između dipiridamola, mopidamola i njihovih farmaceutski prihvatljivih soli, prema potrebi u kombinaciji s jednim ili više drugih antitromboznih sredstava, AGE inhibitorom, angiotenzin II antagonistom, Ca-antagonistom ili sredstvom za sniženje lipida, naznačena time, da se on koristi za proizvodnju farmaceutskog pripravka za liječenje tijela humanog ili ne-humanog bića ili za prevenciju poremećaja mikrocirkulacije ovisnih o fibrinu ili bolesnih stanja u koja su uključeni takovi poremećaji mikrocirkulacije.
11. Upotreba prema zahtjevu 10, naznačen time, da pirimido-pirimidin je dipiridamol.
12. Upotreba prema zahtjevu 10, naznačen time, da je poremećaj mikrocirkulacije ovisan o fibrinu odabran iz skupine koju čine
poremećaj i mikrocirkulacije uzrokovani metaboličkim bolestima u koje su uključena vaskularna oštećenja, kao što je dijabetska angiopatija, posebno dijabetska mikroangiopatija, npr. dijabetska gangrena, dijabetska retinopatija, dijabetska neuropatija ili ulcus cruris,
poremećaji mikrocirkulacije uzrokovani upalnim reakcijama, kao što je Krohnova bolest,
poremećaj i mikrocirkulacij e uzrokovani autoimunosnim bolestima,
kao što je autoimunosni, kronično aktivan hepatitis (idiopatski hepatitis), primarna bilijarna ciroza ili (povezana s autoimunitetom) multipla skleroza,
periferni poremećaji mikrocirkulacije,
kao što je Raynaudova bolest, tinitus ili iznenadan gubitak sluha,
poremećaji mikrocirkulacije povezani s povećanom diobom stanica,
kao što su tumorske bolesti ili trombozno-trombo-citopenična purpura (TTP), i, kao daljnje indikacije,
nefroskleroza,
prerenalna hipertenzija,
hemolitizno-uremijski sindrom (HUS),
arterij ska hipertenzija,
vaskularna demencija,
Alzheimerova bolest,
Sudeckova bolest,
središnja venska tromboza oka, ishemijska optička neuropatija, s homocistmom inducirana vaskulopatija, ishemijske ili koronarne srčane bolesti, prevencija miokardijalnog infarkta ili ponovnog infarkta i
liječenje ili prevencija ateroskleroze.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99121121A EP1093814A1 (en) | 1999-10-22 | 1999-10-22 | Use of dipyridamole or mopidamol in the manufacture of a medicament for the treatment and prevention of fibrin-dependent microcirculation disorders |
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| Publication Number | Publication Date |
|---|---|
| HRP20020342A2 true HRP20020342A2 (en) | 2003-10-31 |
Family
ID=8239263
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| US (2) | US20030149058A1 (hr) |
| EP (2) | EP1093814A1 (hr) |
| JP (1) | JP2003512431A (hr) |
| KR (1) | KR20020040901A (hr) |
| CN (2) | CN1823780A (hr) |
| AR (1) | AR026197A1 (hr) |
| AU (1) | AU784124B2 (hr) |
| BG (1) | BG106609A (hr) |
| BR (1) | BR0014946A (hr) |
| CA (1) | CA2387486C (hr) |
| CZ (1) | CZ20021487A3 (hr) |
| EA (1) | EA200200448A1 (hr) |
| EE (1) | EE200200214A (hr) |
| HK (1) | HK1048597A1 (hr) |
| HR (1) | HRP20020342A2 (hr) |
| HU (1) | HUP0203249A3 (hr) |
| IL (1) | IL148974A0 (hr) |
| MX (1) | MXPA02003901A (hr) |
| NO (1) | NO20021784D0 (hr) |
| NZ (1) | NZ518525A (hr) |
| PE (1) | PE20010747A1 (hr) |
| PL (1) | PL354591A1 (hr) |
| SK (1) | SK7112002A3 (hr) |
| TR (1) | TR200201089T2 (hr) |
| WO (1) | WO2001030353A1 (hr) |
| YU (1) | YU30002A (hr) |
| ZA (1) | ZA200203156B (hr) |
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| US7064130B2 (en) * | 2001-04-20 | 2006-06-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of radical-scavenging compounds for treatment and prevention of NO-dependent microcirculation disorders |
| DE10119680A1 (de) * | 2001-04-20 | 2002-11-14 | Boehringer Ingelheim Pharma | Verwendung von Radikalfänger-Verbindungen zur Behandlung und Verhinderung von no-abhängigen Störungen der Mikrozirkulation |
| WO2003030823A2 (en) | 2001-10-05 | 2003-04-17 | Combinatorx, Incorporated | Combinations for the treatment of immunoinflammatory disorders |
| MY131170A (en) * | 2002-03-28 | 2007-07-31 | Nissan Chemical Ind Ltd | Therapeutic agent for glomerular disease |
| DE10335027A1 (de) * | 2003-07-31 | 2005-02-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Angiotensin II Rezeptor Antagonisten |
| CA2515266A1 (en) * | 2003-02-07 | 2004-08-19 | Boehringer Ingelheim International Gmbh | Use of dipyridamole or mopidamole for treatment and prevention of mmp-9-dependent disorders |
| DE10306179A1 (de) * | 2003-02-13 | 2004-08-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Dipyridamol in Kombination mit Acetylsalicylsäure und einem Angiotensin II-Antagonisten zur Schlaganfall-Prophylaxe |
| BRPI0409796A (pt) * | 2003-04-24 | 2006-05-30 | Boehringer Ingelheim Int | uso de dipiridamol ou mopidamol para tratamento e prevenção de doenças tromboembolìticas e distúrbios provocados pela formação excessiva de trombina e/ou pela expressão elevada de receptores de trombina |
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| WO2005113006A2 (en) | 2004-05-13 | 2005-12-01 | Boehringer Ingelheim International Gmbh | Use of dipyridamole for treatment of resistance to platelet inhibitors |
| PL1750862T3 (pl) | 2004-06-04 | 2011-06-30 | Teva Pharma | Kompozycja farmaceutyczna zawierająca irbesartan |
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| BRPI0409796A (pt) * | 2003-04-24 | 2006-05-30 | Boehringer Ingelheim Int | uso de dipiridamol ou mopidamol para tratamento e prevenção de doenças tromboembolìticas e distúrbios provocados pela formação excessiva de trombina e/ou pela expressão elevada de receptores de trombina |
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1999
- 1999-10-22 EP EP99121121A patent/EP1093814A1/en not_active Withdrawn
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2000
- 2000-10-14 YU YU30002A patent/YU30002A/sh unknown
- 2000-10-14 HU HU0203249A patent/HUP0203249A3/hu unknown
- 2000-10-14 SK SK711-2002A patent/SK7112002A3/sk not_active Application Discontinuation
- 2000-10-14 EA EA200200448A patent/EA200200448A1/ru unknown
- 2000-10-14 NZ NZ518525A patent/NZ518525A/en unknown
- 2000-10-14 KR KR1020027005042A patent/KR20020040901A/ko not_active Application Discontinuation
- 2000-10-14 CN CNA2005101362547A patent/CN1823780A/zh active Pending
- 2000-10-14 PL PL00354591A patent/PL354591A1/xx not_active Application Discontinuation
- 2000-10-14 AU AU12721/01A patent/AU784124B2/en not_active Ceased
- 2000-10-14 IL IL14897400A patent/IL148974A0/xx unknown
- 2000-10-14 EP EP00974393A patent/EP1225900A1/en not_active Withdrawn
- 2000-10-14 CN CNB008146756A patent/CN100411620C/zh not_active Expired - Fee Related
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- 2000-10-14 JP JP2001532773A patent/JP2003512431A/ja active Pending
- 2000-10-14 EE EEP200200214A patent/EE200200214A/xx unknown
- 2000-10-14 BR BR0014946-2A patent/BR0014946A/pt not_active Expired - Fee Related
- 2000-10-14 WO PCT/EP2000/010123 patent/WO2001030353A1/en active IP Right Grant
- 2000-10-14 TR TR2002/01089T patent/TR200201089T2/xx unknown
- 2000-10-14 CA CA002387486A patent/CA2387486C/en not_active Expired - Fee Related
- 2000-10-14 CZ CZ20021487A patent/CZ20021487A3/cs unknown
- 2000-10-20 AR ARP000105541A patent/AR026197A1/es not_active Suspension/Interruption
- 2000-10-20 PE PE2000001127A patent/PE20010747A1/es not_active Application Discontinuation
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2002
- 2002-04-12 BG BG106609A patent/BG106609A/bg active Pending
- 2002-04-16 NO NO20021784A patent/NO20021784D0/no not_active Application Discontinuation
- 2002-04-18 HR HR20020342A patent/HRP20020342A2/hr not_active Application Discontinuation
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2003
- 2003-02-06 HK HK03100835.6A patent/HK1048597A1/zh unknown
- 2003-02-27 US US10/376,072 patent/US20030149058A1/en not_active Abandoned
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2007
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