HRP20020367A2 - Agent for treating hepatitis c - Google Patents
Agent for treating hepatitis c Download PDFInfo
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- HRP20020367A2 HRP20020367A2 HR20020367A HRP20020367A HRP20020367A2 HR P20020367 A2 HRP20020367 A2 HR P20020367A2 HR 20020367 A HR20020367 A HR 20020367A HR P20020367 A HRP20020367 A HR P20020367A HR P20020367 A2 HRP20020367 A2 HR P20020367A2
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- Prior art keywords
- patients
- ukrain
- ifn
- doses
- chc
- Prior art date
Links
- 208000006454 hepatitis Diseases 0.000 title 1
- 231100000283 hepatitis Toxicity 0.000 title 1
- 229930013930 alkaloid Natural products 0.000 claims description 8
- 208000005176 Hepatitis C Diseases 0.000 claims description 7
- 239000012084 conversion product Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 241001233914 Chelidonium majus Species 0.000 claims description 5
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical compound OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 claims description 5
- 108010047761 Interferon-alpha Proteins 0.000 claims description 4
- 102000006992 Interferon-alpha Human genes 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 20
- 108010079944 Interferon-alpha2b Proteins 0.000 description 20
- 208000013772 cryohydrocytosis Diseases 0.000 description 13
- 238000002560 therapeutic procedure Methods 0.000 description 11
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 5
- 108010082126 Alanine transaminase Proteins 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 150000003017 phosphorus Chemical class 0.000 description 3
- 230000008092 positive effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 230000009471 action Effects 0.000 description 2
- 238000003928 amperometric titration Methods 0.000 description 2
- 230000008512 biological response Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KIGCDEJCMKDBHU-NIQQUOCOSA-K ukrain Chemical compound [OH-].[OH-].[OH-].C([C@H](O)[C@@H]1C2=CC=C3OCOC3=C2C2)C3=CC=4OCOC=4C=C3[C@H]1[N+]2(C)CCNP(=S)(NCC[N+]1(C)[C@@H]2C3=CC=4OCOC=4C=C3C[C@H](O)[C@@H]2C2=CC=C3OCOC3=C2C1)NCC[N+]1(C)[C@@H]2C3=CC(OCO4)=C4C=C3C[C@H](O)[C@@H]2C2=CC=C3OCOC3=C2C1 KIGCDEJCMKDBHU-NIQQUOCOSA-K 0.000 description 2
- 241000710781 Flaviviridae Species 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 206010019786 Hepatitis non-A non-B Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- -1 their salts Natural products 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
- A61P31/20—Antivirals for DNA viruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Izum se odnosi na primjenu fosfornih derivata alkaloida za proizvodnju lijeka za liječenje hepatitisa C.
Pod oznakom hepatitis C podrazumijeva se bolest, koja je istražena tek pred relativno kratko vrijeme. Dugo je vremena postojala samo svijest, da se ovdje radi o bolesti, koja izaziva slične simptome kao dosada poznate bolesti hepatitis A i hepatitis B, ali u pojavnom obliku postoje izvjesne bitne razlike. Oboljenje je zbog toga dugo vremena bilo naznačeno pod oznakom "Hepatitis non-A non-B".
Hepatitis C je bolest, koja je široko rasprostranjena osobito u nedovoljno razvijenim zemljama; smatra se, da je u cijelom svijetu oko 170 milijuna ljudi (to je oko četverostruka količina infekcija HIV-om) inficirano hepatitisom C.
Međutim, moglo se istražiti, da virus hepatitisa C pripada porodici Flaviviridae, i u cijelom su svijetu poduzeti veliki napori, da se razvije sredstvo za profilaksu, odnosno za suzbijanje ove bolesti.
AT 377 988 B i AT 354 644 B opisuju postupak za proizvodnju novih fosfornih derivata alkaloida, odnosno novih soli alkaloidnih derivata tiofosforne kiseline. Takvi spojevi imaju farmakološku djelotvornost i mogu se primijeniti kao citostatici.
Sada je iznenađujuće nađeno, da se od supstanci opisanih u navedenim patentnim spisima, za suzbijanje hepatitisa C može primijeniti osobito produkt konverzije alkaloida od Chelidonium majus L. s triazirididom tiofosforne kiseline i da se s jednim takvim sredstvom mogu postići odlični rezultati.
Predmet ovog izuma je stoga primjena produkta konverzije alkaloida od Chelidonium majus L. s triazirididom tiofosforne kiseline za proizvodnju lijeka za suzbijanje hepatitisa C.
Gore navedeni produkt konverzije se u nastavku kratko označava kao "Ukrain"; pretežni sastavni dio Ukraina ima slijedeću formulu:
[image]
Provedena su istraživanja, kod kojih su s jedne strane primijenjeni Ukrain u smjesi s Interferonom-alfa i s druge strane, Ukrain sam. U nastavku trebaju biti opisana oba niza pokusa:
1. Postupak za primjenu Interferona-alfa i Ukraina
Djelovanje rekombinantnog, humanog Interferona-alfa2b (IFN) i Ukraina (polusintetskog spoja alkaloida od Chelidonium majus L. i triaziridida tiofosforne kiseline, NSC-631570, "Nowicky Pharma", Austrija) ispitano je in vitro na omjer tiol-disulfid (SH/SS) krvi (Patent Ruske federacije 2150700) postupkom amperometrijske titracije. Ispitano je 40 CHC-pacijenata. IFN je testiran u dozama od 20, 50, 100, 200, 400, 600, 1000 IE/ml krvi, a Ukrain u dozama od 0,05, 0,1, 0,2, 0,5, 1,0 i 2,0 µg/ml krvi. Izabrano je deset od ispitivanih CHC-pacijenata za klinički pilot-pokus s individualnim optimalnim dozama IFN (0,5 do 2,0 MJ (mjernih jedinica) po injekciji, 6 pacijenata, uključivo 3 slučaja HCV fenotipa 1a) tri puta tjedno i dozama Ukraina (0,25 do 2,5 mg po injekciji, 4 pacijenta, uključivo 2 slučaja HCV 1b) svaki drugi dan.
Pokazalo se, da su reakcije na oba sastojka bile različite: 52,5% svih pacijenata je bilo osjetljivo na IFN, a 73,1% na Ukrain, kod čega je povećanje odnosa SH/SS pod utjecajem sastojaka ocijenjeno kao pozitivno djelovanje, a smanjenje kao negativno djelovanje. Nekoliko pacijenata je već na prvu dozu pripravaka pokazalo pozitivno djelovanje, drugi tek na dvije ili više doza. Češće je registriran optimalni biološki odgovor na IFN u dozama od 400, 200 i 100 IE/ml krvi, a na Ukrain u dozama od 0,5, 0,1 i 0,2 µg/ml krvi.
Standardizirane terapeutske doze IFN od 600 do 1000 IE/ml, koje u injekcijama in vivo odgovaraju dozama od 3,0 do 5,0 MJ, pokazale su pozitivno djelovanje na sustav SH/SS samo u 0 do 18,2% slučajeva, a negativno djelovanje u 63,6 do 81,8% slučajeva, što je jedan od razloga za malu djelotvornost IFN kod CHC i za učestalost nuspojava u terapiji s IFN. Gotovo polovica svih CHC-pacijenata je bila rezistentna na IFN (47,5%), uključivo četiri od slučajeva s dokazanim HCV-fenotipom 1b. Nakon individualne terapije s IFN ili Ukrainom bilo je 9 od 10 pacijenata HCV-RNA negativno metodom PCR: 3 nakon jednog mjeseca, 3 nakon terapije od tri mjeseca s individualnim dozama IFN, 3 nakon trotjedne individualne terapije Ukrainom. Nisu ustanovljene nikakve ozbiljne nuspojave, liječenje svih pacijenata se nastavlja.
Na osnovi ovih dobivenih podataka mogao se već prije terapije staviti na raspolaganje postupak za selekciju pacijenata, koji mogu imati koristi od terapije s IFN ili Ukrainom u određenim optimalnim dozama, i pacijenata, koji na to ne reagiraju, nego se moraju liječiti drugim medikamentima. Individualna terapija će povećati učinkovitost CHC-liječenja, smanjiti broj nuspojava i terapijske troškove držati povoljnijim (na pr. za terapiju s IFN su oni trostruki do peterostruki).
2. Postupak za samostalnu primjenu Ukraina
Djelovanje Ukraina (polusintetskog spoja alkaloida od Chelidonium majus L. i triaziridida tiofosforne kiseline, NSC-631570, "Nowicky Pharma", Austrija,) na omjer tiol-disulfid (SH/SS) krvi (Patent Ruske federacije 2150700) testiran je in vitro postupkom amperometrijske titracije. Ispitano je 26 CHC-pacijenata. Ukrain je testiran u dozama od 0,05, 0,1, 0,2, 0,5, 1,0 i 2,0 µg/ml krvi. Za klinički pilot-pokus s individualnim optimalnim dozama Ukraina (0,25 do 2,5 mg po injekciji), izabrana su svaki drugi dan 4 CHC-pacijenta (2 neliječena pacijenta i 2 pacijenta s dokazanim HCV-fenotipom 1b, koji su prvobitno bili liječeni s Interferonom-alfa).
Dokazano je, da je reakcija na Ukrain bila različita: 73,1% svih pacijenata je bilo osjetljivo na ovaj sastav, dok je u istoj grupi CHC-pacijenata osjetljivost na Interferon-alfa2b (IFN) bila bitno manja, naime 46,2%. U skupini CHC-pacijenata, koji su bili rezistentni na IFN, bila je osjetljivost na Ukrain gotovo jednaka (71,4%), nadalje su sva 4 CHC-pacijenta s HCV-fenotipom 1b osjetljiva na Ukrain in vitro. Često je registriran optimalni biološki odgovor na doze Ukraina od 0,5, 0,1 i 0,2 µg/ml krvi. U kliničkom pokusu mogli smo već nakon 10 injekcija Ukraina ustanoviti pozitivni klinički, biokemijski (smanjenje ALT (alanintransaminaze) u sva 4 slučaja) i virološki odgovor (PCR HCV-RNA je bio u 3 slučaja negativan, uključujući slučaj s HCV 1b). U dva slučaja smanjenju ALT prethodilo je povećanje ALT nakon početka terapije Ukrainom (uključivo u jednom drugom slučaju s HCV 1b, kod čega je ALT bio više nego trostruko smanjen). Serološki omjer SH/SS nakon terapije Ukrainom povisio se u tri slučaja s biokemijskim i virološkim odgovorom, a smanjio se u slučaju bez virološkog odgovora. Nisu utvrđene nikakve nuspojave. Liječenje ova četiri pacijenta se nastavlja.
Utvrđeno je da CHC-pacijenti u velikoj mjeri reagiraju na Ukrain in vitro (1,58-struko više nego na IFN) i da ne postoji unakrsna rezistencija između Ukraina i IFN. Čak i pacijenti s HCV-fenotipom 1b su osjetljivi na Ukrain in vitro i također in vivo. Izgleda, da je individualna terapija CHC pomoću Ukraina djelotvorna i za još neliječene pacijente i za pacijente, koji su rezistentni, ili pretrpe recidiv nakon IFN samog, ili u kombinaciji s Ribavirinom. Na bazi ovih rezultata mogu započeti specijalna klinička ispitivanja s Ukrainom za liječenje CHC-pacijenata.
Lijekovi proizvedeni prema izumu sastoje se prvenstveno iz vodene otopine primijenjenih fosfornih derivata alkaloida, odnosno njihovih soli, po potrebi zajedno s daljnjim, po sebi poznatim pomoćnim tvarima. Davanje lijekova prema izumu provodi se prvenstveno injektiranjem, primjerice intraperitonealno, intramuskularno ili intravenozno, kod čega je doziranje zavisno o slučaju i povezano s težinom oboljenja koje se liječi, kao i sa stanjem pacijenta.
U svakom slučaju o stručnom znanju liječnika koji liječi, ovisi određivanje prikladnog doziranja od slučaja do slučaja.
Claims (2)
1. Primjena produkta konverzije alkaloida od Chelidonium majus L. s triazirididom tiofosforne kiseline, naznačena time, da se ovaj produkt konverzije koristi za proizvodnju lijeka za suzbijanje hepatitisa C.
2. Primjena prema zahtjevu 1, naznačena time, da se produkt konverzije primjenjuje zajedno s drugim djelotvornim supstancama, osobito s Interferonom-alfa.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0048100A AT408719B (de) | 2000-03-22 | 2000-03-22 | Mittel zur behandlung von hepatitis c |
| PCT/AT2001/000076 WO2001070203A2 (de) | 2000-03-22 | 2001-03-20 | Mittel zur behandlung von hepatitis c, enthaltend ukrain |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20020367A2 true HRP20020367A2 (en) | 2004-02-29 |
Family
ID=3674939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20020367A HRP20020367A2 (en) | 2000-03-22 | 2002-04-26 | Agent for treating hepatitis c |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JP2003527414A (hr) |
| KR (1) | KR20020087045A (hr) |
| CN (1) | CN1416347A (hr) |
| AT (1) | AT408719B (hr) |
| AU (1) | AU2001239000A1 (hr) |
| BG (1) | BG107088A (hr) |
| BR (1) | BR0107211A (hr) |
| CA (1) | CA2389173A1 (hr) |
| EA (1) | EA200200584A1 (hr) |
| HR (1) | HRP20020367A2 (hr) |
| IL (1) | IL149314A0 (hr) |
| IS (1) | IS6360A (hr) |
| MA (1) | MA25509A1 (hr) |
| MX (1) | MXPA02004993A (hr) |
| NO (1) | NO20022253D0 (hr) |
| PL (1) | PL365000A1 (hr) |
| WO (1) | WO2001070203A2 (hr) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH695417A5 (de) * | 2001-11-15 | 2006-05-15 | Ddr Wassyl Nowicky Dipl Ing | Verfahren zur Umsetzung von Alkaloiden. |
| EP1459753A1 (en) | 2003-03-18 | 2004-09-22 | Nowicky, Wassyl, Dipl.-Ing. DDr. | Quaternary chelidonine and alkaloid derivatives, process for their preparation and their use in the manufacture of medicaments |
| WO2008039179A1 (en) * | 2006-09-26 | 2008-04-03 | Addiction Research Institute, Inc. | Compositions for the treatment of hepatitis c and methods for using compositions for the treatment of hepatitis c |
| CN106343303A (zh) * | 2015-07-13 | 2017-01-25 | 张如安 | 灭杀乙肝病毒的饮料 |
| CN106109538A (zh) * | 2016-07-29 | 2016-11-16 | 桂林淮安天然保健品开发有限公司 | 治疗丙肝的药物组合物 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3128018A1 (de) * | 1981-07-13 | 1983-04-07 | Wassyl 1060 Wien Nowicky | "verfahren zum diagnostizieren und fuer die therapeutische behandlung von tumoren und/oder infektioesen krankheiten verschiedenster art unter praeparativem einsatz von alkaloid-verbindungen bzw. deren salze" |
| US4816462A (en) * | 1982-05-18 | 1989-03-28 | Nowicky Wassili | Method for diagnosing and for the therapeutic treatment of tumors and/or infectious diseases of different types with alkaloid-compounds |
| US4970212A (en) * | 1982-05-18 | 1990-11-13 | Nowicky Wassili | Method of treating human illnesses which compromise the ability to mount an effective immunological response |
| PT93772A (pt) * | 1989-04-17 | 1991-01-08 | Searle & Co | Processo para a preparacao de composicoes para o tratamento de neoplasias, contendo um agente anti-neoplastico, por exemplo doxorubicina e um agente protector para reduzir os efeitos secundarios, por exemplo carbetimer |
-
2000
- 2000-03-22 AT AT0048100A patent/AT408719B/de not_active IP Right Cessation
-
2001
- 2001-03-20 IL IL14931401A patent/IL149314A0/xx unknown
- 2001-03-20 WO PCT/AT2001/000076 patent/WO2001070203A2/de active Application Filing
- 2001-03-20 CN CN01803046A patent/CN1416347A/zh active Pending
- 2001-03-20 PL PL01365000A patent/PL365000A1/xx not_active Application Discontinuation
- 2001-03-20 CA CA002389173A patent/CA2389173A1/en not_active Abandoned
- 2001-03-20 AU AU2001239000A patent/AU2001239000A1/en not_active Abandoned
- 2001-03-20 KR KR1020027005739A patent/KR20020087045A/ko not_active Application Discontinuation
- 2001-03-20 EA EA200200584A patent/EA200200584A1/ru unknown
- 2001-03-20 BR BR0107211-0A patent/BR0107211A/pt not_active IP Right Cessation
- 2001-03-20 MX MXPA02004993A patent/MXPA02004993A/es unknown
- 2001-03-20 JP JP2001568401A patent/JP2003527414A/ja active Pending
-
2002
- 2002-04-24 IS IS6360A patent/IS6360A/is unknown
- 2002-04-26 HR HR20020367A patent/HRP20020367A2/hr not_active Application Discontinuation
- 2002-05-10 NO NO20022253A patent/NO20022253D0/no unknown
- 2002-05-28 MA MA26657A patent/MA25509A1/fr unknown
- 2002-09-12 BG BG107088A patent/BG107088A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR0107211A (pt) | 2004-01-06 |
| ATA4812000A (de) | 2001-07-15 |
| WO2001070203A2 (de) | 2001-09-27 |
| EA200200584A1 (ru) | 2003-06-26 |
| MXPA02004993A (es) | 2003-10-14 |
| JP2003527414A (ja) | 2003-09-16 |
| IS6360A (is) | 2002-04-24 |
| CA2389173A1 (en) | 2001-09-27 |
| PL365000A1 (en) | 2004-12-27 |
| KR20020087045A (ko) | 2002-11-21 |
| BG107088A (en) | 2003-05-30 |
| IL149314A0 (en) | 2002-11-10 |
| AU2001239000A1 (en) | 2001-10-03 |
| CN1416347A (zh) | 2003-05-07 |
| NO20022253L (no) | 2002-05-10 |
| WO2001070203A3 (de) | 2002-09-06 |
| NO20022253D0 (no) | 2002-05-10 |
| AT408719B (de) | 2002-02-25 |
| MA25509A1 (fr) | 2002-07-01 |
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