HRP20030561A2 - Essentiyal n-3 fatty acids in cardiac insufficiency and heart failure therapy - Google Patents
Essentiyal n-3 fatty acids in cardiac insufficiency and heart failure therapy Download PDFInfo
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- HRP20030561A2 HRP20030561A2 HR20030561A HRP20030561A HRP20030561A2 HR P20030561 A2 HRP20030561 A2 HR P20030561A2 HR 20030561 A HR20030561 A HR 20030561A HR P20030561 A HRP20030561 A HR P20030561A HR P20030561 A2 HRP20030561 A2 HR P20030561A2
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- epa
- dha
- heart failure
- heart
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Classifications
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
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- Veterinary Medicine (AREA)
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- Hospice & Palliative Care (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Ovaj izum pripada polju farmaceutske kemije i kardiovaskularne medicine i osigurava postupak prevencije i upravljanja srčanom insuficijencijom i prestankom rada srca: dvije bolesti srca gdje je ona druga posljedica progresivnog razvoja prve.
Srčana insuficijencija je stanje pri kojem funkcija srčane pumpe nije adekvatna za zadovoljavanje potreba tjelesnog metabolizma. Ovisno o različitim ozbiljnostima nedostataka pumpe, srčana insuficijencija se može manifestirati bez simptoma ili klinički.
Srčana insuficijencija bi mogla imati različite uzroke, npr.:
- poremećaji funkcije miokarda, koji su najčešći uzrok, zbog smanjene sposobnosti stezanja, ali također i zbog gubitka kontraktilnog tkiva;
- opterećenje volumenom, zbog poremećaja koji zahtijevaju da ventrikul protjera više krvi u minuti nego uobičajeno;
- opterećenje tlakom, zbog poremećaja koji povećavaju otpor na otjecanje iz ventrikula.
Zatajenje srca je rezultat progresivnog razvoja srčane insuficijencije.
K tome, širok spektar bolesti može uzrokovati oslabljeno punjenje ili pražnjenje srčanih komora, kao npr.: bolesti koje su posljedice monogenskog (obiteljska hipertrofička kardiomiopatija, mitohondrijske kardiomiopatije) ili multigenskog nedostatka koji ovise o faktorima okoliša kao što su pušenje cigareta, prehrana, fizičko vježbanje, sekundarne bolesti srca. Sve ove bolesti vode uobičajenim putem - prema prestanku rada srca, a taj put se u početku vidi u obliku oslabljenih molekularnih mehanizama, a zatim u obliku oslabljene funkcije ventrikula i prestanka rada srca. Prema tome, zatajenje srca je sindrom s različitom etiologijom koji je posljedica anatomsko-funkcionalne anomalije srca s nemogućnosti održavanja otkucaja koji su adekvatni metaboličkim zahtjevima tkiva ili održavanja količine otkucaja pomoću visokog tlaka punjenja.
Zatajenje srca je karakterizirano kliničkim znakovima i simptomima koji su sekundarni neadekvatnom odgovoru na zahtjeve tjelesnog metabolizma. Ovo stanje bi se moglo pojaviti akutno ili može postati kronično.
Patofiziološke interpretacije prestanka rada srca su vremenom doživjele izuzetan razvoj. Sindrom je smatran za nedostatak pumpe koji je povezan s renalnom disfunkcijom u 50-ima i 60-ima, za disfunkciju pumpe povezanu s povećanjem perifernog otpora u 70-ima i 80-ima, a danas se smatra za prestanak funkcije pumpe koji je povezan s neurohormonalnom aktivacijom čija su posljedica hemodinamska oštećenja koja vode do disfunkcije mnogih organa i sustava.
Sadašnja terapija s lijekovima za srčanu «funkciju pumpe» uključuje uporabu lijekova koji djeluju na različite načine na različitim točkama etiopatogeneze bolesti. Kao primjer spominjemo: ACE-inhibitore (inhibitori Angiotenzin Konvertirajućih Enzima), diuretike, pozitivne inotropne lijekove koji ne sadrže digitalis kao što su adrenergici i inhibitori fosfodiesteraze, vazodilatatore arteriola i venula, npr. hidralazin i izosorbid dinitrat, beta-blokatore npr. metoprolol i bisoprolol, te derivate digitalisa, npr. digotoksin.
Zatajenje srca je danas jedan od najvažnijih uzroka morbiditeta i mortaliteta u industrijaliziranim zemljama, kao što je jasno prikazano sadašnjim serijama studija: u SAD-u 4,7 milijuna ljudi ima kongestivno zatajenje srca, s pojavnosti koja iznosi 400.000 novih slučajeva godišnje.
Prevladavanje kronične srčane insuficijencije se povećava s 8 slučajeva zatajenja srca na 1.000 subjekata koji su stari od 50 do 59 godina, na 66 slučajeva na 1.000 subjekata koji su stari između 80 i 89 godina.
Ukoliko smatramo da je oko 35% pacijenata sa zatajenjem srca hospitalizirano barem jedanput godišnje i da 80% muškaraca i 65% žena umire unutar 6 godina, socijalno-zdravstvena bit problema se pojavljuje u svom punom dramatičnom iskazu.
K tome, pojavnost zatajenja srca se izgleda paradoksalno povećava sa smanjenjem stope smrtnosti za infarkt miokarda i za druge kardiovaskularne bolesti. Starenje populacije je izgleda faktor koji doprinosi povećanju važnosti fenomena.
Prema tome, postoji potreba za sigurnim i prikladnim postupkom prevencije i terapijskog liječenja srčane insuficijencije i zatajenja srca, osobito kod starijih pacijenata, kako bi se ponovo uspostavila (ili kontrolirala) uobičajena funkcija pumpe srca.
Ovaj izum osigurava postupak za prevenciju i terapijsko liječenje srčane insuficijencije i zatajenja srca kod pacijenta kojem je ovakvo liječenje potrebno koji se sastoji od davanja takvom pacijentu terapijski učinkovite količine esencijalne masne kiseline koja sadrži smjesu (20:5ω 3) etil estera eikosapentaenoične kiseline (EPA) i (20:6ω 3) etil estera dokosaheksaenoične kiseline (DHA), bilo zasebno, bilo u kombinaciji s drugim terapijskim sredstvom.
Iskusnim stručnjacima je dobro poznato da neke esencijalne masne kiseline, osobito ω 3 PUFA, koja se nalazi na primjer u ribljem ulju, imaju terapijski učinak u prevenciji i terapiji kardiovaskuralnih poremećaja, npr. u prevenciji i liječenju aterotrombotičkih događaja i hiperlipidemije.
WO 89/11521 posebno opisuje industrijski proces za ekstrakciju smjesa koje imaju visoki sadržaj poli-nezasićenih kiselina, uključujući također EPA i DHA i njihove etil estere, iz životinjskih i/ili biljnih ulja. Smjese masnih kiselina, posebno EPA/DHA, koje su dobivene prema WO 89/11521, su naznačene kao posebno korisne u liječenju kardiovaskularnih patologija.
Prema tome, predmet ovog izuma je uporaba esencijalne masne kiseline koja sadrži smjesu etil estera eikosapentaenoične kiseline (EPA) i etil estera dokosaheksaenoične kiseline (DHA) u pripravi lijeka za prevenciju i liječenje bolesti srca izabrane između srčane insuficijencije i zatajenja srca, i kroničnog i akutnog.
Zbog praktičnosti opisa, etil ester eikosapentaenoične kiseline i etil ester dokosaheksaenoične kiseline se oba ovdje dolje spominju kao «EPA», odnosno «DHA».
Esencijalna masna kiselina, prema izumu, je po mogućnosti masna kiselina koja ima visoki sadržaj EPA i DHA, na primjer sa sadržajem EPA i DHA koji je veći od 25 težinskih %, po mogućnosti od oko 30% do oko 100 težinskih %, osobito oko 85%.
EPA je u EPA/DHA smjesi po mogućnosti prisutna u postotku u rasponu od 25% do oko 45 težinskih %, a DHA je po mogućnosti prisutna u postotku u rasponu od 55% do oko 75 težinskih %.
Pri bilo kojoj vrijednosti, najviše preferirani odnos između EPA i DHA je oko 0,6-1,1/1,3-1,8; osobito oko 0,9/1,5.
Esencijalna masna kiselina se prema ovom izumu može dobiti poznatim postupcima, npr. kao što je opisano u patentima US br. 5.656.667 i WO 89/11521.
Predmet ovog izuma je također uporaba esencijalne masne kiseline koja sadrži smjesu etil estera eikosapentaenoične kiseline (EPA) i etil estera dokosaheksaenoične kiseline (DHA) u pripravi lijeka za prevenciju i liječenje bolesti srca izabrane između srčane insuficijencije i zatajenja srca, i kroničnog i akutnog, gdje lijek služi za kombiniranu terapiju s drugim terapijskim sredstvom.
Izraz «drugo terapijsko sredstvo» označava dodatno pojedinačno sredstvo ili dva ili više dodatnih sredstava, po mogućnosti od 2 do 10, osobito od 2 do 6 prema uputama liječnika, koje se može davati u kombinaciji, tj. bilo zajedno s, bilo odvojeno od (u osnovi simultano ili sekvencijalno) esencijalne masne kiseline koja sadrži smjesu EPA i DHA.
Primjeri terapijskih sredstava za takvu profilaksu ili kombiniranu terapiju prema izumu su ACE-inhibitori, NEP-inhibitori, ACE/NEP-inhibitori, inhibitori angiotenzin II konvertirajućih enzima, diuretici, pozitivni inotropni lijekovi, inhibitori fosfodiesteraze, vazodilatatori arteriola i venula, beta-blokatori i glikozidi digitalisa, ili njihova smjesa.
NEP označava degradacijsku peptidazu atrijskog natriuretskog peptida (ANP).
Primjeri ACE-inhibitora su: kaptopril, enalapril, lisinopril, fosinopril, cilazapril, benazapril, perindopril, kvinapril, ramipril, trandolapril i delapril, osobito cilazapril, kaptopril i enalapril.
Primjeri ACE/NEP-inhibitora su: omapatrilat, sampatrilat i L-fenilalanin,N-[(2S)-2-(merkaptometil)-1-okso-3-fenilpropil]-4-(2-tiazolil) (spoj Z13752A, proizvod Zambon Company).
Primjeri angiotenzin II receptorskih antagonista (angiotenzin II konvertirajući inhibitori) su: kandesartan, valsartan i losartan.
Primjeri diuretika su: hidroklorotiazid, triklormetiazid, klorotiazid, klortalidon, triamteren, klofenamid, furosemid, torasemid, etakrinska kiselina, etozolin, spironolakton i amilorid, ako je primjer zajedno s lijekovima koji čuvaju kalij, koji su dobro poznati iskusnim stručnjacima, osobito furosemid i hidroklorotiazid.
Primjeri dopaminergičkih sredstava su dopamin i ibopamin.
Primjeri inhibitora fosfodiesteraze su: amrinon, milrinon, enoksimon i bucladesin, osobito amrinon i enoksimon.
Primjeri vazodilatatora arteriola i venula su: hidralazin i izosorbid dinitrat.
Primjeri beta-blokatora su: visoprolol, practotol, metoprolol, bucindol, karvedilol, atenolol, bisoprolol, celiprolol i nevibolol, osobito visoprolol, karvedilol i metoprolol.
Primjeri digitalis glikozidnih sredstava su: acetil digitoksin, acetildigoksin, digitoksin, digoksin, lanatozid C, deslanozid, metidigoksin i gitoformat, osobito digitoksin, digoksin, acetildigoksin i metildigoksin.
Primjeri pozitivnih inotropnih sredstava su: pimobendan i vesnarinon, osobito pimobendan.
Daljnjih predmet izuma je postupak za prevenciju i liječenje bolesti srca izabranih između srčane insuficijencije i zatajenja srca, i kroničnog i akutnog, koji se sastoji od davanja pacijentu kojem je to potrebno terapijski učinkovite količine nezasićene esencijalne kiseline koja sadrži smjesu etil estera eikosapentaenoične kiseline (EPA) i etil estera dokosaheksaenoične kiseline (DHA).
Daljnji predmet izuma je postupak za prevenciju i liječenje bolesti srca izabranih između srčane insuficijencije i zatajenja srca, i kroničnog i akutnog, koji se sastoji od davanja pacijentu kojem je to potrebno terapijski učinkovite količine esencijalne masne kiseline koja sadrži smjesu etil estera eikosapentaenoične kiseline (EPA) i etil estera dokosaheksaenoične kiseline (DHA), u kombinaciji s drugim terapijskim sredstvom.
Izraz «u kombinaciji» označava da su esencijalna masna kiselina koja sadrži smjesu EPA+DHA i drugo terapijsko sredstvo dani u takvoj količini i u takvim vremenskim periodima da bi se dobio terapijski učinak.
Uporaba esencijalne masne kiseline prema izumu je izrazito korisna u prevenciji i liječenju srčane insuficijencije i zatajenja srca i kroničnog i akutnog, osobito kod starijih ljudi, npr. starijih od 60 godina, kod subjekata s drugim daljnjim kardiopatskim oblicima i, osobito, kod subjekata koji su preživjeli infarkt miokarda, zahvaljujući činjenici da je to lijek koji se dobro podnosi.
Količina esencijalne masne kiseline koja će se dati pacijentu, bilo kao pojedinačno terapijsko sredstvo ili u kombinaciji s drugim terapijskim sredstvo, ovisi o njenom EPA/DHA sadržaju. Dakle, količina esencijalne masne kiseline koja sadrži EPA/DHA u količini od oko 85%, koja će se dati pacijentu, može varirati od oko 0,7 g do oko 1,5 g dnevno. Preciznije, količina esencijalne masne kiseline, sa sadržajem EPA/DHA od oko 85% i omjerom EPA/DHA od oko 0,9/1,5 je oko 1 g dnevno.
Ova količina proizvoda se može dati u obliku nekoliko doza raspodijeljenih tijekom dana ili, pogodnije, kao pojedinačna doza, kako bi se postigla željena razina u krvi. Naravno, kliničar može mijenjati količinu proizvoda (ili smjese s drugim terapijskim sredstvom) koja će se dati na osnovi stanja pacijenta, dobi i težine.
Količina dodatnog terapijskog sredstva, kada se daje u kombinaciji s esencijalnom masnom kiselinom, je u osnovi količina koju obično primjenjuje kliničar u terapiji. Pri bilo kojoj vrijednosti kliničar može varirati količinu ovog dodatnog lijeka (ili smjese dodatnih lijekova) na osnovi kliničke slike pacijenta.
Kombinirana uporaba esencijalne masne kiseline prema izumu i drugog terapijskog sredstva proizvodi sinergički ili superaditivni učinak, poimence poboljšanje kliničke slike pacijenta koje je zasigurno veće nego ono koje je primijećeno pri davanju zasebno esencijalne masne kiseline ili «drugog terapijskog sredstva». K tome, bolji terapijski učinak pri kombiniranom liječenju ne prati povećana toksičnost.
Prema tome, ovaj izum osigurava kliničaru novi postupak terapijskog liječenja koji je učinkovit za prevenciju i liječenje srčane insuficijencije i zatajenja srca ili barem za poboljšanje stanja pacijenta koji pati od takvih srčanih bolesti ili povećanje njegove/njene kvalitete života. Zaista, na bazi kliničkih markera, koji su danas korisni za razumijevanje različitih faza srčane insuficijencije i progresivne evolucije prema očitom zatajenju srca, kliničar može uporabiti ovaj izum i spriječiti ili barem odgoditi njegov razvoj.
Farmaceutski pripravci prema ovom izumu mogu biti pripravljeni postupcima koji su dobro poznati iskusnim stručnjacima. Preferirani način davanja je oralni, ali liječnik može primijeniti i druge načine davanja, npr. parenteralni.
Terapijsko sredstvo za kombiniranu terapiju, prema ovom izumu, se može pripraviti na način koji je dobro poznat iskusnim stručnjacima.
Esencijalna masna kiselina može biti pripravljena, na primjer, u obliku želatinozne kapsule, kao što je dolje naznačeno.
Želatinozne kapsule
Prema postupcima koji su poznati u farmaceutskoj tehnici kapsule su pripravljene sa sljedećim sastavom i sadrže 1 g aktivnog sastojka (85% EPA-DHA) u svakoj kapsuli.
Pripravak 1.
- EPA etil ester 525 mg/kapsula;
- DHA etil ester 315 mg/kapsula;
- d-alfa-tokoferol 4 IU/kapsula;
- želatina 246 mg/kapsula;
- glicerol 118 mg/kapsula;
- crveni željezni oksid 2,27 mg/kapsula;
- žuti željezni oksid 1,27 mg/kapsula.
Pripravak 2.
- etil esteri poli-nezasićenih masnih kiselina 1000 mg;
- sa sadržajem ω-3 poli-nezasićenih kiselina u etil
esterima (eikosapentaenoične EPA,
dokosaheksaenoične DHA) 850 mg;
- d,l-alfa-tokoferol 0,3 mg;
- sukcinat želatine 233 mg;
- glicerol 67 mg;
- natrij p-hidroksibenzoat 1,09 mg;
- propil natrij p-hidroksibenzoat 0,54 mg.
Claims (19)
1. Uporaba esencijalne masne kiseline, naznačena time, da sadrži smjesu etil estera eikosapentaenoične kiseline (EPA) i etil estera dokosaheksaenoične kiseline (DHA) u pripravi lijeka koji je koristan za prevenciju i liječenje bolesti srca izabrane između srčane insuficijencije i zatajenja srca, i kroničnog i akutnog.
2. Uporaba prema zahtjevu 1, naznačena time, da je lijek za kombiniranu terapiju s drugim terapijskim sredstvom.
3. Uporaba prema zahtjevima 1 ili 2, naznačena time, da je sadržaj EPA+DHA u smjesi veći od 25 težinskih %.
4. Uporaba prema zahtjevu 3, naznačena time, da je sadržaj EPA+DHA od oko 30% i oko 100 težinskih %.
5. Uporaba prema zahtjevu 3, naznačena time, da je sadržaj EPA+DHA oko 85 težinskih %.
6. Uporaba prema zahtjevu 3, naznačena time, da je u smjesi EPA+DHA EPA prisutan u količini u rasponu od oko 25% do oko 45 težinskih % i da je DHA prisutan u količini u rasponu od oko 55% do oko 75 težinskih %.
7. Uporaba prema zahtjevu 3, naznačena time, da je omjer EPA/DHA oko 0,6-1,1/1,3-1,8.
8. Uporaba prema zahtjevu 5, naznačena time, da je omjer EPA/DHA oko 0,9/1,5.
9. Uporaba prema zahtjevu 5, naznačena time, da se esencijalna masna kiselina daje oralnim putem u dozi u rasponu od oko 0,7 g i oko 1,5 g dnevno.
10. Uporaba prema zahtjevu 1 ili 2, naznačena time, da je bolest srca srčana insuficijencija.
11. Uporaba prema zahtjevu 1 ili 2, naznačena time, da je bolest zatajenje srca.
12. Uporaba prema zahtjevu 11, naznačena time, da je zatajenje srca kronično ili akutno.
13. Uporaba prema zahtjevu 2, naznačena time, da je terapijsko sredstvo za kombiniranu terapiju izabrano između ACE-inhibitora, NEP-inhibitora, ACE/NEP-inhibitora, inhibitora angiotenzin II konvertirajućih enzima, diuretika, pozitivnih inotropnih lijekova, inhibitora fosfodiesteraze, vazodilatatora arteriola i venula, beta-blokatora i glikozida digitalisa ili njihove smjese.
14. Uporaba prema zahtjevu 13, naznačena time, da je terapijsko sredstvo za kombiniranu terapiju izabrano između jednog ili više sredstva koja su izabrana između cilazaprila, kaptoprila, enalaprila, kandesartana, valsartana, losartana, furosemida, hidroklorotiazida, dopamina, ibopamina, amrinona, enoksimona, hidralazina, izosorbid dinitrata, visopropola, karvedilola, metoprolola, digitoksina, digoksina, acetildigoksina, metidigoksina, pimobendana, omapatrilata, sampatrilata i spoja Z13752A.
15. Uporaba prema svakom od prethodnih zahtjeva, naznačena time, da je pacijent koji se liječi osoba starija od 60 godina.
16. Uporaba prema svakom od prethodnih zahtjeva, naznačena time, da je pacijent koji se liječi osoba koja pati od drugih kardiopatskih poremećaja.
17. Uporaba prema svakom od prethodnih zahtjeva, naznačena time, da je pacijent koji se liječi osoba koja je preživjela infarkt miokarda.
18. Postupak za prevenciju i liječenje bolesti srca izabrane između srčane insuficijencije i zatajenja srca, i kroničnog i akutnog, naznačen time, da se sastoji od davanja pacijentu kojem je to potrebno terapijski učinkovite količine nezasićene esencijalne kiseline koja sadrži smjesu etil estera eikosapentaenoične kiseline (EPA) i etil estera dokosaheksaenoične kiseline (DHA).
19. Postupak prevencije i liječenja bolesti srca izabrane između srčane insuficijencije i zatajenja srca, i kroničnog i akutnog, naznačen time, da se sastoji od davanja pacijentu kojem je to potrebno terapijski učinkovite količine esencijalne masne kiseline koja sadrži smjesu etil estera eikosapentaenoične kiseline (EPA) i etil estera dokosaheksaenoične kiseline (DHA), u kombinaciji s drugim terapijskim sredstvom.
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| PCT/EP2002/000507 WO2002058793A1 (en) | 2001-01-25 | 2002-01-16 | Essential n-3 fatty acids in cardiac insufficiency and heart failure therapy |
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| US7439267B2 (en) | 2008-10-21 |
| JP2004517148A (ja) | 2004-06-10 |
| EP2258447A3 (en) | 2012-07-25 |
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| PL363269A1 (en) | 2004-11-15 |
| HUP0303019A2 (hu) | 2003-12-29 |
| NZ526609A (en) | 2005-10-28 |
| AU2002225026B2 (en) | 2007-09-13 |
| EP1365841A1 (en) | 2003-12-03 |
| NO20033304D0 (no) | 2003-07-22 |
| CA2433762A1 (en) | 2002-08-01 |
| EP2258447A2 (en) | 2010-12-08 |
| MX282405B (es) | 2010-12-21 |
| CZ20031947A3 (cs) | 2003-12-17 |
| NO20033304L (no) | 2003-07-22 |
| US20040077723A1 (en) | 2004-04-22 |
| SK8332003A3 (en) | 2003-11-04 |
| EE200300297A (et) | 2003-10-15 |
| IS6862A (is) | 2003-06-27 |
| EA200300830A1 (ru) | 2003-12-25 |
| MXPA03006480A (es) | 2003-09-22 |
| ITMI20010129A1 (it) | 2002-07-25 |
| UA78693C2 (en) | 2007-04-25 |
| US20090005327A1 (en) | 2009-01-01 |
| EE05320B1 (et) | 2010-08-16 |
| BG108071A (bg) | 2005-04-30 |
| WO2002058793A1 (en) | 2002-08-01 |
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