HRP20000637A2 - Smilagenin and anzurogenin-d for the treatment of alzheimer's disease - Google Patents
Smilagenin and anzurogenin-d for the treatment of alzheimer's disease Download PDFInfo
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- HRP20000637A2 HRP20000637A2 HR20000637A HRP20000637A HRP20000637A2 HR P20000637 A2 HRP20000637 A2 HR P20000637A2 HR 20000637 A HR20000637 A HR 20000637A HR P20000637 A HRP20000637 A HR P20000637A HR P20000637 A2 HRP20000637 A2 HR P20000637A2
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Description
Ovaj izum odnosi se na smilagenin i anzurogeni-D, te na njegovu primjenu u liječenju kognitivnih poremećaja i povezanih stanja; kao i na mješavine koje se koriste kod takvih liječenja. Ovaj izum odnosi se na liječenje stanja koje karakterizira nedostatak odgovarajuće količine odnosno funkcije receptora vezanih na membranu. U nastavku izuma bit će opisan prvenstveno izvještaj o liječenje Alzheimerove bolesti (AD) i senilne demencije Alzheimerovog tipa (SDAT), gdje je prikazan nedostatak odgovarajuće količine tipova receptora. Potrebno je shvatiti kako se ovaj izum općenito odnosi na liječenje stanja koja se mogu pripisati prirođenim patološkim stanjima i/ili izlaganju različitim uvjetima iz okoliša koje karakterizira nedostatak odgovarajuće količine odnosno funkcije receptora vezanih na membranu ili nedostatak prijenosa na spojevima između neurona ili spojevima između neurona i efektora.
Gore navedeni uvjeti odnose se na Parkinsonovu bolest, demenciju Lewi-jevog tijela, posturalnu hipotenziju, autizam, sindrom kroničnog umora, miasteniju gravis, Lambert Eatonovu bolest, te probleme povezane sa sindromom Zaljevskog rata, velikim izlaganjem organofosfornim spojevima, kao i staračkim problemima.
Alzheimerova bolest (AD) i senilna demencija Alzheimerovog tipa (SDAT) teški su i rastući problemi u svim društvima u kojima se zbog produljenja životnog vijeka i nadzora nad iznenadnim bolestima demografski dijagram pojačano pomiče u korist starije populacije. Stoga su agensi koji mogu liječiti odnosno pomoći u kontroli AD/SDAT hitno potrebni.
Slabljenje pamćenja povezano sa starošću (AAMI) karakteristično je za starije pacijente koji su psihički i fizički normalni, a žale se na gubitak pamćenja. To je slabo definirani sindrom, no agensi koji su djelotvorni u liječenju AD/SDAT također mogu biti dragocjeni i ovim pacijentima.
Ispitivanje AD/SDAT izvodi se pomoću tradicionalnih i konvencionalnih medicinskih ispitivanja i disciplina. Konvencionalna medicina poznaje nekoliko pristupa liječenju AD/SDAT. Poznato je da su biokemijski procesi koji potpomažu pamćenje u cerebralnom korteksu (barem djelomično) kolinergijski posredovani. Stručnjaci znaju da se “kolinergijski posredovani” mehanizmi mogu direktno pripisati acetilkolinu koji djeluje na receptore i ima direktan učinak. Ostali klinički korisni učinci mogu također biti izazvani modulacijom otpuštanja acetilkolina iz završetaka presinaptičkih krajeva živaca ili inhibicijom enzima koji uništavaju acetilkolin. Ti modulacijski faktori mogu se očitovati preko neurona pri čemu je posrednik nekolinergik; to se odnosi na indirektne učinke. Neki pokušaji u postupku liječenja usredotočili su se na ulogu drugih posrednika poput 5-hidroksitriptamina koji je posrednik u drugim dijelovima mozga, kao što su jezgre srednjeg mozga. S obzirom da su vlakna iz tih područja projicirana prema cerebralnom korteksu gdje je primarni prenositelj acetilkolin, pozornost je bila usredotočena na upravljanje tim posrednikom kako bi se pronašli odgovarajući terapijski agensi.
Kolinergijske strategije koje su se koristile za liječenje AD/SDAT bile su usmjerene na nekoliko točaka na putu nastajanja, sinaptičkog otpuštanja i uklanjanja otpuštenog acetilkolina.
Jedan pristup uključuje liječenje visokim dozama lecitina i drugih prekursora acetilkolina. Taj pristup ima ograničenu uporabu s obzirom na nastajanje produljenih poboljšanja kognitivne performanse.
Drugačiji pristup uključuje uporabu biljnih droga poput ekstrakta iz korijena Polygalae, za koju se pokazalo da povisuje aktivnost kolin-acetilkolin transferaze (CAT) i izlučivanje faktora živčanog rasta (NGF). Oralnom primjenom NGF ne dolazi ni do kakvog učinka na neurone središnjeg živčanog sustava jer je to protein velike molekulske mase koji ne može prijeći kroz hemolikvornu barijeru. Agensi koji mogu prijeći kroz hemolikvornu barijeru, a imaju stimulirajući učinak na sintezu NGF u središnjem živčanom sustavu, predloženi su za poboljšanje načina funkcioniranja pamćenja.
Rezultati trećeg kliničkog pristupa, koji koristi kolinesterazu kao inhibitor takrin hidroklorida, nisu bitno bolji od gore navedenih. Pokazalo se da su tvari koje se koriste u kineskoj i zapadnoj medicini, a dobivene su iz biljaka, kao što su npr. huperzin, galantamin i fizostigmin, djelotvorne - iako ograničeno - u postupku liječenja AD/SDAT u kliničkim proučavanjima, kao i kod laboratorijskih modela. Sve su te tvari inhibitori acetilkolinesteraze (AChE). Kod pacijenata koji boluju od AD/SDAT može doći do smanjene sinteze acetilkolina (ACh), smanjene djelotvornosti pri otpuštanju ACh iz presinaptičkih depoa, kao i do smanjenja količine ili funkcije postsinaptičkih (M1) receptora. Pokazalo se također da dolazi i do smanjenja kod presinaptičkih M2 receptora. Koristan učinak AChE inhibitora pripisuje se povećanju razine acetilkolina na sinapsama u mozgu zbog usporenog uništavanja otpuštenih prijenosnika.
Poznato je da mješavine koje moduliraju kolinergijsku funkciju utječu na pamćenje i sjećanje. Na primjer nikotin stimulira receptore nikotin acetilkolina, te se smatra da su pojačani učinci na kratkotrajno pamćenje ovisni o djelovanju nikotina. Skopolamin je antagonist acetilkolina koji uzrokuje amneziju i slabljenje funkcije pamćenja, što se manifestira kao produljenje jednostavnih vremenskih perioda potrebnih za reagiranje u psihomotornim ispitivanjima, vjerojatno kao rezultat smanjenje pažnje, te se stoga koristi u dodatnom analgezijskom liječenju. Nikotin može antagonistički djelovati na amnezijski učinak skopolamina.
Postoje dvije porodice podtipova nikotinskih receptora (α i β), a svaki uključuje četiri podskupine koje se razlikuju s obzirom na specifičnost liganada. Uloga nikotinskih receptora u središnjem živčanom sustavu nije dobro razjašnjena na molekulskoj razini. Moguće je da tvari koje se vežu na nikotinske receptore modificiraju brzinu prijenosa na muskarinskim receptorskim mjestima u mozgu. Nikotinski receptori su ionski kanali “zatvoreni” ligandom, a njihova aktivacija uzrokuje brzo (u milisekundama) povećanje stanične propusnosti za Na+ i Ca2+, depolarizaciju i ekscitaciju.
Slijedeća skupina kolinergijskih receptora može se stimulirati pomoću muskarina. Takvi receptori muskarina (M) su G protein spareni receptori. Reakcije receptora muskarina su sporije, a mogu biti ekscitatorske ili inhibitorske. Oni nisu nužno povezani s promjenom ionske propusnosti. Otkriveno je 5 vrsta receptora muskarina pomoću kolinergijskog kloniranja receptora, a označeni su kao m1-m5. Farmakološki učinci povezani su s četiri klonirana receptora, te su označeni s M1-M4, što se odnosi na farmakološku specifičnost.
Pomoću specifičnih proteinskih receptora i monoklonskih antitijela bilo je u mozgu moguće daljnje lokaliziranje receptora muskarina kao m1 (postsinaptički) i m2 (presinaptički). U srcu su M2 receptori postsinaptički. Smatra se da presinaptički receptori muskarina imaju inhibicijsko djelovanje, a vezanje ACh na te receptore slabi otpuštanje daljnjeg ACh, što uzrokuje negativni povratni mehanizam kod ACh otpuštanja. Selektivni M2 antagonisti receptora, koji su preferencijano raspoređeni u mozgu, mogu biti korisni u liječenju Alzheimerove bolesti.
Poznato je da kod stanja bolesti kao što su AD/SDAT dolazi do općenitog gubitka neurona i nedostatka kolinergijske živčane funkcije. Nagađalo se da se veliki afinitet veznih mjesta prema nikotinu kod preostalih kolinergijskih neurona može promijeniti u mali afinitet veznih mjesta kod liječenja takvih bolesti odgađanjem otpuštanja prijenosnika. Smanjivanjem afiniteta veznih mjesta za nikotin, izbjegava se brzi desenzibilizacijski proces.
Aktivacija agonista na receptorima nikotina u mozgu ima brzi početak i svršetak. Smanjeni afinitet receptora nikotina smanjit će desenzibilizacijski proces. R. D. Schwarz i suradnici (J. Neuro Chem 42, (1984), 1495-8) pokazali su da su vezna mjesta nikotina presinaptički locirana na kolinergijskim krajevima aksona (kao i također 5-hidroksitriptaminergijskim i kateholaminergijskim). Promjena velikog afiniteta veznih mjesta kod AD/SDAT može također prouzročiti promjenu modulatornog učinka kojeg vezna mjesta za nikotin mogu imati na ostale prijenosne sustave.
GABAergijski živci također inhibicijski kontroliraju presinaptičke kolinergijske mehanizme, te se smatra da ta inhibicija pojačava presinaptičku kortikalnu kolinergijsku aktivnost i pojačava kognitivni proces.
Međudjelovanja intraneuronskih vlakana uzrokovana nikotinom (smanjenje afiniteta vezanja) i ne-inhibicija GABAergijskih vlakana imaju presinaptički lokus.
To je simplificirani model središnjeg prijenosa, ali stvara okvir koji omogućava razumijevanje pokušaja napravljenih kako bi se povećala djelotvorna koncentracija acetilkolina u središnjim sinapsama. To nadalje oslikava koncept posrednog i neposrednog djelovanja. Postoje određeni nedostaci vezani uz tri gore navedena konvencionalna terapeutska pristupa liječenju bolesti AD/SDAT: nadomjestak ACh prekursora, zamjena agonista i inhibicija acetilkolinesteraze. Ti postupci liječenja mogu dovesti do kratkotrajnog povećanja količine dostupnog ACh koji može aktivirati povratni mehanizam, što dovodi do desenzibilizacije postsinaptičkih receptora. Teorijski gledano, dugotrajna korist ne može se predvidjeti, a ako se liječenje prekine, bilo kakav pozitivni učinak u vezi s nadzorom nad AD/SDAT i AAMI nestaje, te se stanje može čak i pogoršati.
Pokazalo se da spojevi s M1 agonističkim i M2/M3 antagonističkim djelovanjem poboljšavaju kognitivnu performansu kod pacijenata koji boluju od SDAT (Sramak i suradnici, Life Science vol. 2, br. 3, 195-202, 1997). Ovaj spoj uzrokuje neprihvatljive kolinergijske neželjene učinke poput umora, proljeva i mučnine.
Radikalniji pristup u odnosu na AD/SDAT teži povećanju količine postsinaptičkih receptora (M1) u mozgu. Poznato je iz Kineskog patenta br. CN1096031A da sarasapogenin (SaG) može regulirati povišenje M1 kolinergijskih receptora, kao i regulirati snižavanje (npr. pomaknuti prema normalnoj razini) β-androgenih receptora čiji broj može biti patološki povišen kod AD/SDAT.
Objavljene su patentne prijave koje tvrde da su steroidi sapogenina sa strukturama spirostana, furo-spirostana, spirosolana ili solanidina nekorisni za postupak liječenja bolesti uključujući i SDAT. Ovdje su dvije patentne publikacije od posebnog značenja: publikacija Kineskog patenta br. CN 1096031A zahtijeva uporabu spirostan sapogenina, sarsasapogenina u liječenju SDAT. Priopćenje u tom dokumentu vrlo je kratko. Slijedeći značajni dokument predstavlja publikacija patenta DE 4303214A1 koja zahtijeva uporabu vrlo širokog spektra saponina i sapogenina za liječenje cijelog niza bolesti za koje izumitelji smatraju da su virusnog podrijetla. To priopćenje ima sumnjivu vrijednost s obzirom da je vrlo dobro poznato da ne postoji nikakav infektivni faktor kod velikog mnoštva stanja koje karakterizira nedostatak sinaptičkog prijenosa, te je stoga osnovna pretpostavka navedenog izuma propala. Nadalje, oni ne daju nikakve podatke koji bi omogućili stručnjaku da bude u stanju odabrati pogodnu tvar iz ogromnog mnoštva koje je navedeno u zahtjevu.
Izumitelji su pronašli da smilagenin (SMI) i anzurogenin D (AZD) mogu regulirati receptore. Pronađeno je da ti spojevi, posebice SMI, povećavaju količinu M2receptora u mozgu. Stoga, prema jednom aspektu izuma, osigurana je uporaba jednog ili više spojeva iz skupine koju čine smilagenini i/ili anzurogenin D u proizvodnji lijekova koji se koriste za liječenje stanja okarakteriziranih nedostatkom dovoljne količine postsinaptičkih receptora vezanih na membranu odnosno nedostatkom njihove funkcije.
Stručnjaci se mogu uvjeriti u odnos između saponina i njihovih sapogenina, kao i da se željeni učinak sapogenina može vidjeti na pacijentima kojima se daju odgovarajući saponini, odnosno njihove smjese. Do hidrolize određene količine saponina dolazi u gastrointestinalnom traktu. Stručnjak se također može uvjeriti u epimerizaciju odgovarajućih sapogenina u uvjetima kisele hidrolize.
Zanimljivi sapogenini iz ovog izuma imaju slijedeću opću formula:
[image]
S obzirom na opću formulu, struktura SMI-a i AZD-a prikazana je u tablici koja slijedi:
[image]
Saponini i sapogenini koji su od primarnog interesa s obzirom na odgovarajuće aspekte ovog izuma pojavljuju se u prirodi u nizu biljnih vrsta, većinom iz roda Smilax, Asparagus, Anemarrhena, Yucca ili Agava. Najinteresantnije vrste uključuju Smilax regelii Kilip & Morton - pod uobičajenim nazivom honduraška sarsaparilla; Smilax aristolochiaefolia Miller - pod uobičajenim nazivom meksička sarsaparilla; Smilax ornata Hooker - pod uobičajenim nazivom jamajčanska sarsaparilla; Smilax aspera - pod uobičajenim nazivom španjolska sarsaparilla; Smilax glabra Roxburgh; Smilax febrifuga - Kunth - pod uobičajenim nazivom ekvadorska ili peruanska sarsaparilla; Anemarrhena asphodeloides Bunge; Yucca schidigera Roezel ex Ortgies; i Yucca brevifolia Engelm.
U skladu s daljnjim aspektima ovog izuma, pripravljena je farmaceutska mješavina sa svojstvima koja povećavaju kognitivnu funkciju, a koja uključuje djelotvornu količinu smilagenina i/ili anzurogenina D.
S druge strane, izum daje farmaceutske mješavine sa svojstvima koja povećavaju kognitivnu funkciju, a koja uključuje djelotvornu količinu smilagenina i/ili anzurogenina D dobiven iz biljnih porodica Smilax, Asparagus, Anemarrhena, Yucca ili Agava.
Bilo bi poželjno da u svojim okvirima izum obuhvati uporabu ranije navedenih mješavina. Stoga, a u skladu s petim aspektom, ovaj izum opisuje metodu za unapređenje kognitivne funkcije koja uključuje primjenu djelotvorne doze mješavine na ljudima ili životinjama navedene u ovom izumu.
Ovaj izum opisuje metodu za unapređenje kognitivne funkcije kod ljudi i životinja koja uključuje davanje djelotvorne doze smilagenina i/ili anzurogenina D.
Ovdje korišten pojam “kognitivna funkcija” odnosi se na funkcije kao što su mišljenje, razumijevanje, pamćenje, zamišljanje i učenje.
Kod identifikacijskih spojeva koji bi se mogle koristiti u liječenju SDAT i drugih bolesti karakteriziranih smanjenjem količine receptora ili sinaptičkog prijenosa, izumitelji su obratili pozornost na potrebu identifikacije spojeva koji bi mogli imati željeni učinak, ali bi bili lišeni ikakvog estrogenog učinka, koji bi bio neprihvatljiv, posebno kod muških pacijenata. Kod određenog broja spojeva, kod kojih je zahtjevana aktivnost, u Patentnoj prijavi DE 4303214A1 primijećeno je estrogeno djelovanje, te su stoga neprihvatljivi. Ovi spojevi ispitivani su u nastavku na ostale steroidne receptore s obzirom da se smatralo da spojevi koji bi mogli imati kliničku primjenu ne bi trebali djelovati na ostale steroidne receptore. Nije pronađeno da niti jedna tvar ima ikakvo djelovanje na bilo koji od
slijedećih receptora:
progesteron
glukokortikoid
testosteron
Odabranim spojevima također je ispitivano djelovanje u nizu in-vitro određivanja: Provedena ispitivanja/pokusi, za koje se smatralo da su od ključne važnosti za određivanje mogućeg djelovanja u podizanju količine receptora vezanih na membranu, bili su:
1. Stanice jajnika kineskog hrčka (CHO) transfektirane su s DNA fragmentnim kodom za receptor muskarina. Stanični niz korišten za većinu pokusa bio je takav niz koji vrši ekspresiju m2 receptora.
2. Ispitivani su učinci ekspresije receptora muskarina u uzgojenim staničnim nizovima neuronskog podrijetla.
3. Uzgojene su stanice srčanog mišića dobivene od novorođenih Sprague Dawley štakora. Stanice srčanog mišića vrše ekspresiju receptora muskarina, uobičajeno m2. Razina tih receptora pada kod produljenih kultura, te su ispitivani učinci zanimljivih spojeva na sprečavanje pada količine receptora.
Slijedi opis metoda i rezultata pokusa .
1 CHO pokusi na staničnom nizu
Ispitivani su učinci različitih spojeva na ekspresiju m2 receptora na CHO stanice transfektirane s DNA za m2 receptor. Količina receptora određena je uporabom QNB obilježenog tricijem te oduzimanjem nespecifičnog vezanja. Spojevi su otopljeni u DMSO, a DMSO se također koristi za usporedbu. Spojevi su ispitivani u području konačnih koncentracija. Spojevi su također ispitivani u prisustvu i odsustvu tamoksifena kako bi se pokušalo razlikovati mehanizam kojim upravlja estrogeni receptor. Podaci su skupno prikazani u Tablici 2. koja slijedi u nastavku, u kojoj su spojevi korišteni u izumu otisnuti podebljano, a podaci za druge sapogenine dani su radi usporedbe.
Tablica 2. Učinci spojeva na ekspresiju m2 receptota na CHO stanice
[image]
NS = nema signifikantnog značajnog utjecaja
U pokusima se pokazalo da nekoliko spojeva može povećati količinu receptora muskarina kod kojih je došlo do ekspresije na površini stanica CHO uzgojenih in-vitro. Tamoksifen nije imao antagonističko djelovanje, što je upućivalo na činjenicu da uključeni mehanizam nije uključivao estrogeni receptor
2 Učinak spojeva na preživljavanje stanica
Druga in vitro određivanja uporabljena su kako bi se odredili učinci smilagenina i anzurogenina D. Različiti stanični nizovi neuroblastoma uzgojeni su in vitro, uključujući i SKN-SN i SH-SY5Y stanice, kao i stanični nizovi fakromoacitoma u prisustvu β-amiloidnih fragmenata ili pražnjenja seruma. Ispitivan je niz tehnika s kojima se željela pokazati učinkovitost spojeva u zaštiti uzgojenih stanica. Te su tehnike uključile tripan plavu ekskluziju, kemiluminiscenciju i otpuštanje laktatdehidrogenaze. Najzanimljivije je bilo promatranje inkubacije stanica, a posebno PC12 stanica, s β-amiloidom koji je smanjivao količinu receptora muskarina pomoću tehnike vezivanja s radioaktivnoobilježenim ligandom. Pronađeno je da smilagenin i anzurogenin D pozitivno utječu na smanjenje količine receptora.
3 Učinci spojeva na uzgojene stanice srčanog mišića
Stanice srčanog mišića izolirane su iz ventrikularnog mišića novorođenih Sprague Dawley štakora pomoću standardnih tehnika. Stanice su uzgajane in vitro, te je pomoću specifičnog vezanja QNB-a obilježenog tricijem određivana količina receptora muskarina na kojima je izvršena ekspresija na površini fragmenata membrane nakon homogenizacije stanica skupljenih u različitim vremenskim razmacima. Preliminarni pokusi pokazali su da je količina receptora na kojima je izvršena ekspresija imala tendenciju otklona 10 dana nakon uzgoja. Stoga su pokusi bili oblikovani tako da ispitaju učinak različitih spojeva na inhibiciju ovog otklona s obzirom na količinu receptora.
Podaci su skupno prikazani u Tablici 3, u kojoj su spojevi korišteni u izumu otisnuti podebljano, a podaci za druge sapogenine dani su radi usporedbe.:
Tablica 3. Učinci različitih spojeva na ekspresiju receptota muskarina na uzgojene stanice srčanog mišića
[image]
NS = nema značajnog utjecaja
Ovdje se nagađa da učinak djelatne tvari koja se zahtjeva u ovom patentu može djelovati preko učinka G proteina, te da je učinak na količinu receptora sekundaran u odnosu na učinak na G-protein. Kada dolazi do stimulacije receptora vezanog na membranu na kojeg se spojio G-protein dolazi do dva osnovna niza događaja: odgovor činitelja; te internalizacija receptora. Postoji mnoštvo faktora o kojima ovisi prevođenje receptora u takvo stanje u kojem se ponovno nalazi na površini stanice ili površini neke druge membrane, gdje može stupiti u interakciju s nekim drugim ligandom. Izgleda da je mnoštvo tih faktora ili mehanizama vezano s G-proteinom. Postoji dokaz da aktivacija m3 receptora može utjecati na ekspresiju ili na razinu G-proteina. Pretpostavlja se da djelovanje spojeva opisanih u ovom patentu može dovesti do interakcije u postupku regeneracije receptora, G-proteinske veze ili G-proteinske homeostaze.
Druga pretpostavka je da spojevi povećavaju sintezu odnosno otpuštanje odnosno smanjenje stupnja razgradnje neurotropnih faktora, kao što je faktor rasta koji potječe iz mozga i/ili faktor živčanog rasta. Taj učinak na faktor rasta može potjecati od učinka spoja na citosolni receptor ili receptor jezgre, ili od vezanja spoja na promotorsko područje koji direktno ima posljedični učinak na povećanje proizvodnje mRNA za faktor rasta, ili kao posljedica povećane proizvodnje neke druge vrste faktora, kao što je G-protein, ili pak konačni učinak može biti sekundaran u odnosu na učinak na receptor ili na procesiranje G-proteina.
Claims (13)
1. Uporaba smilagenina u proizvodnji lijeka, naznačena time, da povećava količinu muskarinskih receptora ili unapređuje funkciju muskarinskih receptora kod ljudi i životinja.
2. Uporaba anzurogenina D u proizvodnji lijeka, naznačena time, da povećava količinu muskarinskih receptora ili unapređuje funkciju muskarinskih receptora kod ljudi i životinja.
3. Kombinirana uporaba smilagenina i anzurogenina D u proizvodnji lijeka, naznačena time, da povećava količinu muskarinskih receptora ili unapređuje funkciju muskarinskih receptora kod ljudi i životinja.
4. Uporaba prema bilo kojem od prethodnih zahtjeva, naznačena time, da je navedeni lijek namijenjen liječenju kognitivne disfunkcije.
5. Uporaba prema bilo kojem od prethodnih zahtjeva, naznačena time, da je navedeni lijek namijenjen unapređenju kognitivne funkcije kod pacijenata koji pate od kognitivne disfunkcije uzrokovane starošću.
6. Uporaba prema bilo kojem od prethodnih zahtjeva, naznačena time, da je navedeni lijek namijenjen liječenju odabranih bolesti: Alzheimerova bolest, senilna demencija Alzheimerovog tipa, Parkinsonova bolest, demencija Lewi-jevog tijela, posturalna hipotenzija, autizam, sindrom kroničnog umora, mijastenija gravis, Lambert Eaton-ova bolest, problemi povezani sa sindromom Zaljevskog rata, velika izlaganja organofosfornim spojevima, te starački problemi.
7. Uporaba prema bilo kojem od prethodnih zahtjeva, naznačena time, da je navedeni lijek namijenjen za liječenje Alzheimerove bolesti ili senilne demencije Alzheimerovog tipa.
8. Uporaba prema bilo kojem od zahtjeva 1, 3, 4 do 7, naznačena time, da se smilagenin nalazi u ekstraktu dobivenom iz biljke koja spada u porodicu Smilax, Asparagus, Anemarrhena, Yucca ili Agava.
9. Farmaceutska mješavina, naznačena time, da uključuje farmakološki djelatnu količinu anzurogenina D.
10. Farmaceutska mješavina, naznačena time, da uključuje farmakološki djelatnu količinu smilagenina.
11. Uporaba prema bilo kojem zahtjevu od 2 do 8 ili mješavina prema zahtjevu 9 ili 10, naznačena time, da se anzurogenin-D nalazi u ekstraktu dobivenom iz biljke koja spada u porodicu Smilax, Asparagus, Anemarrhena, Yucca ili Agava.
12. Neterapeutska metoda unapređenja kognitivne funkcije kod ljudi ili životinja, naznačena time, da uključuje davanje djelotvorne količine smilagenina i/ili anzurogenina-D.
13. Uporaba smilagenina i/ili anzurogenina-D u proizvodnji hrane ili pića, naznačena time, da služi unapređenju kognitivne funkcije.
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| PCT/GB1999/000960 WO1999048482A2 (en) | 1998-03-26 | 1999-03-26 | Smilagenin and anzurogenin-d for the treatment of alzheimer's disease |
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