SI9200406A - Bradykinin antagonists for treatment of acute pancreatitis - Google Patents
Bradykinin antagonists for treatment of acute pancreatitis Download PDFInfo
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- SI9200406A SI9200406A SI19929200406A SI9200406A SI9200406A SI 9200406 A SI9200406 A SI 9200406A SI 19929200406 A SI19929200406 A SI 19929200406A SI 9200406 A SI9200406 A SI 9200406A SI 9200406 A SI9200406 A SI 9200406A
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 208000034526 bruise Diseases 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229930190815 caerulein Natural products 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960001706 ceruletide Drugs 0.000 description 1
- 229940107137 cholecystokinin Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000019626 lipase activity Nutrition 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 210000004923 pancreatic tissue Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000008728 vascular permeability 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
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/043—Kallidins; Bradykinins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
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- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/18—Kallidins; Bradykinins; Related peptides
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
Antagonisti bradikinina za zdravljenje akutnega pankreatitisa
Izum se nanaša na uporabo antagonistov bradikinina ali njihovih fiziološko prenesljivih soli za zdravljenje akutnega pankreatitisa, na farmacevtska sredstva, ki jih vsebujejo, in na njihovo uporabo za pripravo primernih farmacevtskih pripravkov.
Dolgo so mislili, da je bradikinin udeležen pri akutnem pankreatitisu. Leta 1989 pa so Berg et al. ovrgli to hipotezo. Berg et al. so dokazali (The Journal of Pharmacology and Experimental Therapeutics, Vol. 251, No. 2 (1989) str. 731-734), da D-Arg°Hyp3-Thi5,8-D-Phe7-BK-(D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg) ne vpliva na hipotenzijo, ki jo povzroči nastanek akutnega pankreatitisa pri podganah.
Presenetljivo smo ugotovili, da so peptidi, ki so primerni za zdravljenje akutnega pankreatitisa, tisti s formulo I
R1-A-B-C-E-F-G - J-K-R2 (I), v kateri
R1 pomeni vodik, C1-C4-alkanoil, ki je lahko substituiran z merkapto, hidroksifenilom, (4-benzoil)fenoksi ali pomeni (4-benzoil)benzoil-Lys;
A pomeni D-Arg ali D-Lys ali stoji za direktno vez;
B pomeni Arg, ki je lahko substituiran z NO2 ali toluen-4-sulfonilom ali pomeni
Lys, ki je lahko substituiran s toluen-4-sulfonilom ali CO-NH-C6H5, ali stoji za direktno vez;
C pomeni Hyp-Pro-Gly, Pro-Hyp-Gly, Pro-Pro-Gly ali dehidroPro-Hyp-Gly;
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E pomeni Thi, Phe, Leu ali Cha;
F pomeni Ser ali Cys;
G pomeni D-Tic, D-Phe ali D-Hyp, substituiran s C^C^alkoksi;
J pomeni Tic, Aoc ali Oic;
K pomeni Arg ali Ahx ali stoji za direktno vez;
R2 je hidroksi ali amino;
in njihove fiziološko prenesljive soli.
Če ni navedeno drugače, stoji kratica za aminokislinski radikal ali iminokislinski radikal brez stereodeskriptorja za radikal v L-obliki, kot npr. za
Ahx e-aminoheksanoil
Aoc cis, endo-2-azabiciklo[3.30]oktan-3-S-karbonil
Arg arginin
Cha cikloheksilalanin
Cys cistein
Gly glicin
Hyp hidroksiprolin
HypE(transmetil) 4-hidroksiprolin-trans-metileter
HypE(transpropil) 4-hidroksiprolin-trans-propileter
Leu levcin
Lys lizin
Oic cis, endo oktahidroindol-karbonil
Phe fenilalanin
Pro prolin
Thi 2-tienilalanin
Tic l,2,3,4-tetrahidroizokinolin-3-il-karbonil
Tyr tirozin
Nekateri od teh aminokislinskih radikalov ali iminokislinskih radikalov so opisani v EP-A 370 453 (HOE 88/F 328K).
Prednostno izvedbena oblika obsega uporabo peptidov s formulo I, v kateri R1 pomeni vodik, acetil, kije lahko substituiran z merkapto ali (4-benzoil)fenoksi ali pomeni (4-benzoil)benzoil-Lys;
A pomeni D-Arg ali stoji za direktno vez;
B pomeni Arg, ki je lahko substituiran s toluen-4-sulfonilom ali stoji za
211292 direktno vez;
C pomeni Pro-Hyp-Gly, Pro-Pro-Gly ali dehidroPro-Hyp-Gly;
E pomeni Thi, Phe ali Leu;
F pomeni Ser ali Cys;
G pomeni D-Tic, D-Phe ali D-HypE(transmetil) ali D-HypE(transpropil);
J pomeni Tic, Aoc ali Oic;
K pomeni Arg in
R2 je hidroksi;
in njihovih fiziološko prenesljivih soli.
Posebno prednostna izvedbena oblika obsega uporabo peptidov s formulo I, v kateri R1 pomeni vodik ali (4-benzoil)benzoil-Lys;
A pomeni D-Arg;
B pomeni Arg;
C pomeni Pro-Hyp-Gly ali Pro-Pro-Gly;
E pomeni Thi, Phe ali Leu;
F pomeni Ser;
G pomeni D-Tic ali D-HypE(transpropil);
J pomeni Oic;
K pomeni Arg in
R2 je hidroksi;
in njihovih fiziološko prenesljivih soli.
Prav posebno prednostna je uporaba teh-le peptidov s formulo I
H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
H-D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
H-D-Arg-Arg-Pro-Hip-Gly-Phe-Ser-D-Tic-Oic-Arg-OH,
SEQ ID NO:1 SEQ ID NO:2 SEQIDNO:3
H-(4-benzoil)benzoil-Lys-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
SEQ ID NO:4
H-D-Arg-Arg-Pro-Hyp-Gly-Leu-Ser-D-Tic-Oic-Arg-OH, SEQ ID NO:5 H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-HypE(transpropil)-Oic-Arg-OH in njihovih fiziološko prenesljivih soli.
Peptide s formulo I lahko pripravimo npr. tako, da
SEQ ID NO:6
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a) presnovimo fragment, ki ima C-terminalno prosto karboksilno skupino ali njen aktiviran derivat, s primernim fragmentom, ki ima N-terminalno prosto amino skupino, ali
b) sintetiziramo peptid postopno, pri čemer v danem primeru odcepimo eno ali več zaščitnih skupin, ki smo jih začasno uvedli za zaščito drugih funkcij v spojini, dobljeni v skladu z (a) ali (b), in v danem primeru pretvorimo tako dobljene spojine s formulo I v njihove fiziološko prenesljive soli, ali tako, kot je opisano v EP-A 370 453 (HOE 88/F 328K), EP-A 413 277 (HOE 89/F 261), EP-A 455 133 (HOE 90/F 131) ali v Journal of Medicinal Chemistry, 1991, Vol. 34, No. 8, strani 2649-2653.
Peptide s formulo I lahko zlahka pretvorimo v ustrezne soli z alkalijskimi kovinami, zemeljskoalkalijskimi kovinami, fiziološko prenesljivimi amini in anorganskimi ali organskimi kislinami, kot npr. s HC1, HBr, H2SO4, H3PO4, maleinsko kislino, fumarno kislino, citronsko kislino, vinsko kislino in ocetno kislino. Soli lahko uporabimo v skladu z izumom.
Peptidi s formulo I so uporabni pri zdravljenju akutnega penkreatitisa, za katerega so značilni masivni edem žleznega in retroperitonealnega tkiva, intersticialna aktivacija proteolitskih encimov, porast nivojev amilaze in lipaze v serumu, hipovolemija, hipoalbuminemija, pljučni edem in močne bolečine.
Eksperimentalni poskusi:
Substance: Peptid s formulo I, cerulein (CRL, Sigma, U.S.A.) in bradikinin (Bachem, Švica) smo raztopili v fiziološki raztopini v koncentraciji 1 mM. Kalikrein iz prašičjega pankreasa (Sigma, U.S.A.) smo raztopili v 50%-nem (vfv) etanolu in razredčili s 154 mM raztopino NaCl. Pentobarbiton natrij (®Nembutal) smo kupili pri firmi Sanofi (Francija). Fenobarbiton natrij smo dobili od firme Apoka (Avstrija) in vsak dan sveže raztopili v koncentraciji 80 mg/ml v 154 mM raztopini natrijevega klorida. Kaptopril smo dobili od firme Squibb von Heyden GmbH (Avstrija). Evansovo modrilo smo kupili pri firmi Sigma (U.S.A.).
Peptid s formulo I (tabele 1-3):
A: H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH
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Statistična analiza: Primerjali smo hipotenzivni učinek bradikinina in kalikreina pri kuncu pred in po peptidu s formulo I ob uporabi Quadejevega testa (Conover W.J.: Practical nonparametric statistics, 2nd ed. New York, Wiley, 1980, 295-299). Primerjave med 4 obdelanimi skupinami pri podgani smo opravili z neparametričnimi multiplimi primerjavami (Zar J.H.: Biostatistical Analysis, 2nd ed. Englewood Cliffs, Prentice-Hall, 1984).
1. Dokaz za inhibicijo endogensko nastalega bradikinina:
Metode: Kunce obeh spolov (3,5-5,0 kg) smo anestetizirali s pentobarbiton natrijem (35 mg/kg i.v.). Arterijski krvni tlak smo kontrolirali v arteriji karotis ob uporabi Stathamovega pretvornika tlaka. V jugularno veno smo v presledkih po 10 min intravensko injicirali bradikinin (1-10 nmol/kg) ali kalikrein (1 do 10 U/kg). Intravensko smo dali peptid s formulo I (3 nmol/kg) in nato ponovili injekcije bradikinina ali kalikreina.
Rezultati: Kratki padec krvnega tlaka, ki sta ga izzvala bradikinin in kalikrein celo v dozah 10 nmol/kg bradikinina oz. 10 U/kg kalikreina, je bil popolnoma blokiran z obdelavo z peptidom A. Rezultati jasno dokazujejo, da je ne samo injicirani bradikinin, temveč tudi bradikinin, ki ga odcepi iz kininogena kalikrein, popolnoma inhibiral peptid s formulo I (peptid A).
2. Zdravljenje eksperimentalnega pankreatitisa pri podganah:
Splošne metode: Za indukcijo eksperimentalnega pankreatitisa v živalih smo uporabili vrsto postopkov, vključno podvezovanje pankreasnega voda, infuzijo oleinske kisline ali infuzijo analoga amfibijskega holecistokinina, ceruleina. Zadnje navedeni postopek povzroči hiperstimulacijo eksokrine funkcije pankreasa in vodi do morfoloških sprememb, ki kažejo številne značilnosti, ki jih opazimo tudi pri humanem akutnem pankreatitisu (Willemer S., Bialek R., Kohler H. Adler G; Caerulein-induced acute pancreatitis in rats: changes in glycoprotein-composition of subcellular membrane systems in acinar celiš; Histochemistry 1990; 95; 87-96). S ceruleinom inducirani pankreatitis pri podganah smo uporabili za tele poskuse.
1 1 292
Učinki na krvni tlak pri podganah:
Metoda: Podganje samice Sprague-Dawley (260±30 g) smo anestetizirali s pentobarbiton natrijem (40 mg/kg, i.p.) in fenobarbiton natrijem (160 mg/kg, i.p.). Istočasno smo injicirali kaptopril (50 mol/kg, i.p.), da bi povečali učinke sproščenih kininov z inhibicijo kininaze II, kije aktivna v mnogih tkivih (Lembeck F., Griesbacher T., Eckhardt M.; Demonstration of extrapulmonary activity of angiotensin converting enzyme in intact tissue preparations; Br.J. Pharmacol. 1990, 100, 49-54). 10 min kasneje smo dali živalim subkutano (s.c.) injekcijo peptida s formulo I (100 nmol/kg) ali ustrezen volumen (0,5 ml/kg) 154 mM raztopine natrijevega klorida. Sistemski arterijski krvni tlak smo kontrolirali v arteriji karotis ob uporabi Stathamovega pretvornika tlaka. V jugularno veno smo uvedli kanilo, da smo omogočili infuzijo ceruleina (4 nmol/kg/h) ali fiziološke raztopine (0,034 ml/min). Z infuzijo smo začeli 30 min po s.c. injekciji peptida s formulo I ali fiziološke raztopine in trajala je 2 h. Na koncu poskusa smo živali usmrtili z dekapitacijo; kri smo zbrali za določitev amilaze in lipaze v serumu.
Rezultati: Intravenska infuzija ceruleina (4 nmol/kg/min) je inducirala zmanjšanje krvnega tlaka. Ustrezne vrednosti, dobljene z živalmi, obdelanimi s peptidom s formulo I (100 nmol/kg, s.c., 30 min pred začetkom infuzije ceruleina) in vrednosti, dobljene v kontrolah, so navedene v tabeli 1:
| Tabela 1 | Krvni tlak | |||
| Obdelava z | infuzija | padec krvnega tlaka | ||
| A | 0-120 min | 40-105 min po začetku infuzije CRL | ||
| ne | NaCl | 16 ±3 | 1 | |
| ne | CRL | 38 ±3 | [ n.s. | * 1 |
| da | NaCl | 13 ±1 | J | ** |
| da | CRL | 16 ±4 | 1 |
Srednje vrednosti ± SEM. Signifikanca razlike med skupinami, naznačenimi z oklepaji: * P < 0,02; ** P < 0,01; n.s. = ni signifikantno; n=10 za vsako skupino.
Rezultat kaže, da je obdelava s peptidom A zmanjšala s CRL inducirani padec krvnega tlaka na obseg kontrolnih vrednosti. Obdelava s peptidom A brez infuzije
1 1 292
CRL se ni razlikovala od infuzije NaCl kot kontrole.
Učinki na pankreasni edem:
Metoda: Kvantificiranje pankreasnega edema smo dosegli z merjenjem suhe mase pankreasa in kopičenja plazemskih proteinov v pankreasu. Ob koncu infuzij (glej poskuse s krvnim tlakom) smo kri zbrali, da bi izmerili encime v serumu. Pankreas smo izrezali in stehtali. Po sušenju tkiva smo uporabili razliko med mokro in suho maso v odnosu na suho maso kot merilo za vsebnost vode v tkivu. Neposredno pred začetkom i.v. infuzije ceruleina ali fiziološke raztopine smo injicirali i.v. 5 mg/kg Evansovega modrila, ki se kvantitativno veže na serumski albumin (Rawson RA: The binding of T-1824 and structurally related diazo dyes by plasma proteins, Amer. J. Physiol. 1943, 138, 708-717). Nato smo pankreasno tkivo uporabili, da smo fotometrično izmerili koncentracijo Evansovega modrila (Gamse R., Holzer P., Lembeck F.: Decrease of substance P in primary afferent neurones and impairment of neurogenic plasma extravasation by capsaicin, Br.J.Pharmacol. 1980, 68, 207-213; Saria A., Lundberg J.M.: Evans blue fluorescence: quantitative and morphological evaluation of vascular permeability in animal tissues, J.Neurosci.Meth. 1983, 8, 4149). Kontrolne živali smo obdelali z ustreznimi volumni fiziološke raztopine namesto peptida s formulo I ali ceruleina. Plazemsko ekstravazacijo smo kvantificirali kot vsebnost vode in Evansovega modrila v pankreasu.
Rezultati: Tabela 2 Pankreasni edem pri podganah
| A | CRL | voda | Evansovo modrilo |
| [sc.] | [iv·] | [g/g suhe mase] | |ju,g/g suhe mase] |
| ne | ne | 2,50 ± 0,24 | 16,96 ± 3,26 1 |
| ne | da | 7,28 ±0,61 ] | '*** 478,51 ± 79,94 ] J ** |
| da | ne | 2,62 ±0,23 [** 20,31 ±5,80 [* | |
| da | da | 3,11 ± 0,33 J | 18,21 ± 4,24 J |
Srednje vrednosti ± SEM. Signifikanca razlike med skupinami, naznačenimi z oklepaji: * P < 0,05; ** P < 0,01; *** P < 0,001; n = 10 v vsaki skupini.
Obdelava s peptidom A je popolnoma inhibirala s CRL inducirani pankreasni edem.
1 1 292
Vpliv na koncentracijo pankreasnih encimov v serumu:
Metode: Serumsko amilazo smo določili ob uporabi kinetičnega barvnega testa z 2-kloro-4-nitrofenil-D-maltoheptozidom (komplet za test amilaze firme Roche, ZRN). Serumsko lipazo smo izmerili z zmanjšanjem motnosti zaradi cepitve trioleina v monoglicerid in oleinsko kislino (Monotest Lipase, Boehringer Mannheim, ZRN). Meji detekcije za amilazo in lipazo sta bili 11 U/l oz. 16 U/l. Kontrolne živali smo obdelali z ustreznimi volumni fiziološke raztopine namesto peptida s formulo I.
Rezultati: Tabela 3 aktivnosti serumskih encimov pri podganah
| A | CRL | Amilaza | Lipaza | |||
| [sc.] | [iv·] | [U/ml] | [U/ml] | |||
| ne | ne | 2,95 ± 0,29 | nn | |||
| ne | da | 10,40 ± 1,14 | 1 | * | 1,51 ±1,14 j | * |
| da | ne | 3,19 ± 0,21 | [* | nn [* | ||
| da | da | 57,17 ± 16,11 | J | 16,33 ±4,50 J |
Srednje vrednosti ± SEM. Signifikanca razlike med skupinami, naznačenimi z oklepaji: * P < 0,05; n = 6 v vsaki skupini; nn = ni določljivo.
Obdelava s peptidom A je signifikantno povečala s CRL inducirane poraste aktivnosti amilaze in lipaze pri krvnem tlaku.
Če povzamemo, pokazalo se je, da se pri eksperimentalnem pankreatitisu, induciranem s CRL, sprošča bradikinin. Bradikinin inducira hipotenzijo in pankreasni edem. CRL povzroči tudi porast pankreasnih encimov v serumu. Peptidi s formulo I preprečujejo z bradikininom inducirani edem in s tem omogočajo pankreatskim encimom, da neovirano zapuste tkivo. Zato zmanjšuje kasnejše patološke pojave v pankreasu. S tem smo dokazali, da so peptidi s formulo I uporabni pri zdravljenju akutnega pankreatitisa.
Dodatno smo za primerjavo s peptidom A preizkusili D-Arg°-Hyp3-This,8-D-Phe7BK, ki so ga opisali Berg et al. (glej stran 1). Oba antagonista smo dali dvema skupinama podgan pod enakimi pogoji 10 minut po začetku infuzije ceruleina. Medtem ko je peptid A popolnoma inhibiral porast vsebnosti vode in Evansovega modrila v pankreasu, je bil antagonist, ki so opisali Berg et al., popolnoma
1 1 292 neučinkovit, če smo ga dali v 10-krat večji dozi kot peptid A.
Izum nadalje obsega uporabo peptidov v skladu z izumom za pripravo farmacevtskih pripravkov, kijih uporabljamo za zdravljenje akutnega pankreatitisa pri sesalcih, kot pri ljudeh itd.
Farmacevtske pripravke pripravimo po postopkih, ki so sami po sebi in strokovnjaku znani. Kot farmacevtske pripravke uporabljamo farmakološko aktivne spojine (= učinkovine) v skladu z izumom bodisi kot take ali prednostno v kombinaciji s primernimi farmacevtskimi pomožnimi snovmi v obliki raztopin, v katerih znaša vsebnost učinkovine do okoli 95%, prednostno med 10 in 75%.
Pomožne snovi, ki so primerne za želeni farmacevtski pripravek, so strokovnjaku na osnovi njegovega strokovnega znanja znane. Poleg topil in drugih nosilcev za učinkovino lahko uporabimo npr. antioksidante, dispergente, konservirna sredstva ali sulubilizima sredstva.
Učinkovine lahko dajemo parenteralno, t.j. kot subkutano, intramuskulamo ali intravensko injekcijo ali infuzijo. Doziranje učinkovine je odvisno od vrste sesalca, telesne mase, starosti in načina dajanja.
Farmacevtske pripravke v smislu pričujočega izuma pripravimo v raztopini ob uporabi samih po sebi znanih postopkov.
Za intravensko, subkutano ali intramuskulamo dajanje raztopimo spojine ali njihove fiziološko prenesljive soli, po želji s farmacevtskimi običajnimi pomožnimi snovmi, npr. za dosego izotoničnosti ali uravnavanje pH, in solubilizatorje, emulagatorje in druge pomožne snovi.
Primerno dozirno območje za oblike vseh vrst sistemičnega dajanja je 0,01 do 1 mg/kg.
1 1 292
Primeri:
1. Raztopina za injekcijo ali infuzijo
H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH 5,00 mg ocetna kislina 6,2 mg natrijev acetat x 3 H2O 115,5 mg natrijev klorid 835,0 mg voda za injekcije ad 100,0 ml
Raztopino naravnamo na pH 5,5.
2. Raztopina za injekcijo ali infuzijo
H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH 250,0 mg ocetna kislina 6,2 mg natrijev acetat x 3 H2O 115,5 mg natrijev klorid 835,0 mg voda za injekcije ad 100,0 ml
Raztopino naravnamo na pH 5,5.
1 1 292
Seznam sekvenc:
SEQIDNO. 1
TIP SEKVENCE: amino kisline (naravne in umetne) DOLŽINA SEKVENCE: 10 amino kislin VERIŽNOST: enojna
TOPOLOGIJA: linearna
TIP MOLEKULE: peptid
PRVOTNI VIR: gani
ORGANIZEM: gani
NEPOSREDNI EKSPERIMENTALNI VIR: sintetična
D-Arg Arg Pro Xaa Arg Pro
Hyp Gly Thy Ser D-Tic Oic Arg 3Hyp Gly Xaa Ser Xaa Xaa Arg
10
SEQ ID NO. 2
TIP SEKVENCE: amino kisline (naravne in umetne)
DOLŽINA SEKVENCE: 10 amino kislin
VERIŽNOST: enojna
TOPOLOGIJA: linearna
TIP MOLEKULE: peptid
PRVOTNI VIR: gani
ORGANIZEM: ga ni
NEPOSREDNI EKSPERIMENTALNI VIR: sintetična
D-Arg Arg Pro Pro Gly Thy Ser D-Tic Oic Arg
Xaa Arg Pro Pro Gly Xaa Ser Xaa Xaa Arg
10
1 1 292
SEOIDNO. 3
TIP SEKVENCE: amino kisline (naravne in umetne) DOLŽINA SEKVENCE: 10 amino kislin VERIŽNOST: enojna
TOPOLOGIJA: linearna
TIP MOLEKULE: peptid
PRVOTNI VIR: ga ni
ORGANIZEM: ga ni
NEPOSREDNI EKSPERIMENTALNI VIR: sintetična
D-Arg Arg Pro Xaa Arg Pro
Hyp Gly Phe Ser D-Tic Oic Arg 3Hyp Gly Phe Ser Xaa Xaa Arg
10
SEQ ID NO. 4
TIP SEKVENCE: amino kisline (naravne in umetne)
DOLŽINA SEKVENCE: 10 amino kislin
VERIŽNOST: enojna
TOPOLOGIJA: linearna
TIP MOLEKULE: peptid
PRVOTNI VIR: ga ni
ORGANIZEM: ga ni
NEPOSREDNI EKSPERIMENTALNI VIR: sintetična (4-benzoil)benzoil)Lys D-Arg Arg Pro Hyp Gly Thi SerD-Tic Arg
Xaa Arg Pro 3Hyp Gly Xaa SerXaa
Claims (9)
1. Farmacevtski pripravek za uporabo za zdravljenje akutnega pankreatitisa, označen s tem, da vsebuje farmakološko aktivno množino peptida s formulo I
R1 - A-B-C-E-F-G-J-K-R2 (I) v kateri
R1 pomeni vodik, C^-C^-alkanoil, ki je lahko substituiran z merkapto, hidroksifenilom, (4-benzoil)fenoksi ali pomeni (4-benzoil)benzoil-Lys;
A pomeni D-Arg ali D-Lys ali stoji za direktno vez;
B pomeni Arg, ki je lahko substituiran z NO2 ali toluen-4-sulfonilom ali pomeni
Lys, ki je lahko substituiran s toluen-4-sulfonilom ali CO-NH-C6H5, ali stoji za direktno vez;
C pomeni Hyp-Pro-Gly, Pro-Hyp-Gly, Pro-Pro-Gly ali dehidroPro-Hyp-Gly;
E pomeni Thi, Phe, Leu ali Cha;
F pomeni Ser ali Cys;
G pomeni D-Tic, D-Phe ali D-Hyp, substituiran s C^-C^-alkoksi;
J pomeni Tic, Aoc ali Oic;
K pomeni Arg ali Ahx ali stoji za direktno vez;
R2 je hidroksi ali amino;
ali njegove fiziološko prenesljive soli v farmacevtsko sprejemljivem nosilcu.
2. Pripravek po zahtevku 1, označen s tem, da uporabimo peptid s formulo I, v kateri
R1 pomeni vodik, acetil, kije lahko substituiran z merkapto ali (4-benzoil)fenoksi ali pomeni (4-benzoil)benzoil-Lys;
A pomeni D-Arg ali stoji za direktno vez;
B pomeni Arg, ki je lahko substituiran s toluen-4-sulfonilom ali stoji za direktno vez;
C pomeni Pro-Hyp-Gly, Pro-Pro-Gly ali dehidroPro-Hyp-Gly;
E pomeni Thi, Phe ali Leu;
F pomeni Ser ali Cys;
G pomeni D-Tic, D-Phe ali D-HypE(transmetil) ali D-HypE(transpropil);
J pomeni Tic, Aoc ali Oic;
K pomeni Arg in
R2 je hidroksi
2 11 2 bi.
ali njegovo fiziološko prenesljivo sol.
3. Pripravek po zahtevku 1 ali 2, označen s tem, da uporabimo peptid s formulo I, v kateri
R1 pomeni vodik ali (4-benzoil)benzoil-Lys;
A pomeni D-Arg;
B pomeni Arg,;
C pomeni Pro-Hyp-Gly ali Pro-Pro-Gly;
E pomeni Thi, Phe ali Leu;
F pomeni Ser;
G pomeni D-Tic ali D-HypE(transpropil);
J pomeni Oic;
K pomeni Arg in
R2 je hidroksi;
in njegovo fiziološko prenesljivo sol.
4. Pripravek po zahtevku 1 do 3, označen s tem, da uporabimo
H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
H-D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
H-D-Arg-Arg-Pro-Hip-Gly-Phe-Ser-D-Tic-Oic-Arg-OH,
SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3
H-(4-benzoil)benzoil-Lys-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
SEQ ID NO:4
H-D-Arg-Arg-Pro-Hyp-Gly-Leu-Ser-D-Tic-Oic-Arg-OH, SEQ ID NO:5 H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-HypE(transpropil)-Oic-Arg-OH
SEQ ID NO:6 in njihovo fiziološko prenesljivo sol.
5. Uporaba peptida s formulo I
R1-A-B-C-E-F-G-J-K-R2 (I), v kateri
R1 pomeni vodik, C1-C4-alkanoil, ki je lahko substituiran z merkapto, hidroksifenilom, (4-benzoil)fenoksi ali pomeni (4-benzoil)benzoil-Lys;
A pomeni D-Arg ali D-Lys ali stoji za direktno vez;
211292
B pomeni Arg, ki je lahko substituiran z NO2 ali toluen-4-sulfonilom ali pomeni Lys, ki je lahko substituiran s toluen-4-sulfonilom ali CO-NH-C6H5, ali stoji za direktno vez;
C pomeni Hyp-Pro-Gly, Pro-Hyp-Gly, Pro-Pro-Gly ali dehidroPro-Hyp-Gly;
E pomeni Thi, Phe, Leu ali Cha;
F pomeni Ser ali Cys;
G pomeni D-Tic, D-Phe ali D-Hyp, substituiran s C^-C^-alkoksi;
J pomeni Tic, Aoc ali Oic;
K pomeni Arg ali Ahx ali stoji za direktno vez;
R2 je hidroksi ali amino;
ali njegove fiziološko prenesljive soli za zdravljenje akutnega pankreatitisa.
6. Uporaba peptida s formulo I po zahtevku 5, v kateri
R1 pomeni vodik, acetil, ki je lahko substituiran z merkapto ali (4-benzoil)fenoksi ali pomeni (4-benzoil)benzoil-Lys;
A pomeni D-Arg ali stoji za direktno vez;
B pomeni Arg, ki je lahko substituiran s toluen-4-sulfonilom ali stoji za direktno vez;
C pomeni Pro-Hyp-Gly, Pro-Pro-Gly ali dehidroPro-Hyp-Gly;
E pomeni Thi, Phe ali Leu;
F pomeni Ser ali Cys;
G pomeni D-Tic, D-Phe ali D-HypE(transmetil) ali D-HypE(transpropil);
J pomeni Tic, Aoc ali Oic;
K pomeni Arg in
R2 je hidroksi;
ali njegove fiziološko prenesljive soli.
7. Uporaba peptida s formulo I po zahtevkih 5 ali 6, kjer
R1 pomeni vodik ali (4-benzoil)benzoil-Lys;
A pomeni D-Arg;
B pomeni Arg,;
C pomeni Pro-Hyp-Gly, ali Pro-Pro-Gly;
E pomeni Thi, Phe ali Leu;
F pomeni Ser;
G pomeni D-Tic ali D-HypE(transpropil);
8. Uporaba peptida s formulo I po zahtevkih 1 do 7 iz niza, ki obsega
H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
H-D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
H-D-Arg-Arg-Pro-Hip-Gly-Phe-Ser-D-Tic-Oic-Arg-OH,
SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3
H-(4-benzoil)benzoil-Lys-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH,
SEQ ID NO:4
H-D-Arg-Arg-Pro-Hyp-Gly-Leu-Ser-D-Tic-Oic-Arg-OH, SEQ ID NO:5 H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-HypE(transpropil)-Oic-Arg-OH
SEQ ID NO:6 in njihove fiziološko prenesljive soli za zdravljenje akutnega pankreatitisa.
9. Postopek za pripravo farmacevtskega sredstva po zahtevku 1 do 4, označen s tem, da pretvorimo aktivno snov v primerno dozirno obliko s primernimi ekscipienti, pomožnimi snovmi in/ali dodatki.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP91122055 | 1991-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI9200406A true SI9200406A (en) | 1993-06-30 |
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ID=8207466
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI19929200406A SI9200406A (en) | 1991-12-21 | 1992-12-21 | Bradykinin antagonists for treatment of acute pancreatitis |
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| Country | Link |
|---|---|
| US (1) | US5670619A (sl) |
| EP (1) | EP0548825B1 (sl) |
| JP (1) | JP3588472B2 (sl) |
| KR (1) | KR930012034A (sl) |
| CN (1) | CN1073603A (sl) |
| AT (1) | ATE152733T1 (sl) |
| AU (1) | AU662188B2 (sl) |
| BG (1) | BG97168A (sl) |
| BR (1) | BR9205062A (sl) |
| CA (1) | CA2085781C (sl) |
| CY (1) | CY2116B1 (sl) |
| CZ (1) | CZ375692A3 (sl) |
| DE (1) | DE69219574T2 (sl) |
| DK (1) | DK0548825T3 (sl) |
| ES (1) | ES2101017T3 (sl) |
| FI (1) | FI925782A (sl) |
| GR (1) | GR3024179T3 (sl) |
| HU (1) | HU214056B (sl) |
| IL (1) | IL104163A0 (sl) |
| MA (1) | MA22743A1 (sl) |
| MX (1) | MX9207440A (sl) |
| NO (1) | NO924925L (sl) |
| PL (1) | PL297044A1 (sl) |
| SI (1) | SI9200406A (sl) |
| TW (1) | TW199863B (sl) |
| YU (1) | YU108192A (sl) |
| ZA (1) | ZA929829B (sl) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US7105172B1 (en) | 1999-11-18 | 2006-09-12 | Bolla John D | Treatment of rosacea |
| US20040248809A1 (en) * | 2003-02-07 | 2004-12-09 | Aventis Pharma Deutschland Gmbh | Use of antagonists of the bradykinin B2 receptor for the treatment of osteoarthrosis |
| RU2425669C1 (ru) * | 2010-04-13 | 2011-08-10 | Общество С Ограниченной Ответственностью "Гамаветфарм" | Средство для профилактики и лечения острого и хронического панкреатита |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0009010B1 (en) * | 1978-07-18 | 1983-03-02 | Kabi AB | Bradykinin inhibiting tripeptide derivatives, process for their preparation and pharmaceutical preparations containing them |
| US4693993A (en) * | 1985-06-13 | 1987-09-15 | Stewart John M | Bradykinin antagonist peptides |
| US4801613A (en) * | 1985-06-13 | 1989-01-31 | Nova Technology Limited Partnership | Bradykinin antagonist peptides |
| US4923963A (en) * | 1987-09-02 | 1990-05-08 | Nova Technology Limited Partnership | Bradykinin antagonist peptides |
| US5162497A (en) * | 1987-09-24 | 1992-11-10 | The Administrators Of The Tulane Educational Fund | Bradykinin analogs with non-peptide bond |
| DE4013270A1 (de) * | 1990-04-26 | 1991-10-31 | Hoechst Ag | Peptide mit bradykinin-antagonistischer wirkung |
| DE3926822A1 (de) * | 1989-08-14 | 1991-02-21 | Hoechst Ag | Peptide mit bradykinin-antagonistischer wirkung |
| IE63490B1 (en) * | 1988-11-24 | 1995-05-03 | Hoechst Ag | Peptides having bradykinin antagonist action |
| DE69012142D1 (de) * | 1989-12-08 | 1994-10-06 | Univ Boston | Acylierte bradykininantagonisten und deren verwendung. |
| EP0451791A2 (de) * | 1990-04-12 | 1991-10-16 | Hoechst Aktiengesellschaft | Langwirksame Liposomenpräparate von Peptidarzneistoffen und Verfahren zu ihrer Herstellung |
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1992
- 1992-03-26 TW TW081102310A patent/TW199863B/zh active
- 1992-12-14 BG BG097168A patent/BG97168A/bg unknown
- 1992-12-16 MA MA23033A patent/MA22743A1/fr unknown
- 1992-12-17 PL PL29704492A patent/PL297044A1/xx unknown
- 1992-12-17 AU AU30212/92A patent/AU662188B2/en not_active Ceased
- 1992-12-18 NO NO92924925A patent/NO924925L/no unknown
- 1992-12-18 AT AT92121558T patent/ATE152733T1/de active
- 1992-12-18 DK DK92121558.8T patent/DK0548825T3/da active
- 1992-12-18 ES ES92121558T patent/ES2101017T3/es not_active Expired - Lifetime
- 1992-12-18 YU YU108192A patent/YU108192A/sh unknown
- 1992-12-18 DE DE69219574T patent/DE69219574T2/de not_active Expired - Lifetime
- 1992-12-18 ZA ZA929829A patent/ZA929829B/xx unknown
- 1992-12-18 FI FI925782A patent/FI925782A/fi unknown
- 1992-12-18 CA CA002085781A patent/CA2085781C/en not_active Expired - Lifetime
- 1992-12-18 BR BR9205062A patent/BR9205062A/pt not_active Application Discontinuation
- 1992-12-18 MX MX9207440A patent/MX9207440A/es unknown
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- 1992-12-18 JP JP33773592A patent/JP3588472B2/ja not_active Expired - Lifetime
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- 1992-12-19 KR KR1019920024742A patent/KR930012034A/ko not_active Application Discontinuation
- 1992-12-21 SI SI19929200406A patent/SI9200406A/sl unknown
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- 1992-12-21 CN CN92114564A patent/CN1073603A/zh active Pending
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Also Published As
| Publication number | Publication date |
|---|---|
| ES2101017T3 (es) | 1997-07-01 |
| ZA929829B (en) | 1994-02-16 |
| JPH05255107A (ja) | 1993-10-05 |
| AU662188B2 (en) | 1995-08-24 |
| FI925782A0 (fi) | 1992-12-18 |
| DE69219574D1 (de) | 1997-06-12 |
| BR9205062A (pt) | 1993-09-28 |
| MX9207440A (es) | 1993-07-01 |
| FI925782A (fi) | 1993-06-22 |
| JP3588472B2 (ja) | 2004-11-10 |
| EP0548825A1 (en) | 1993-06-30 |
| NO924925D0 (no) | 1992-12-18 |
| DK0548825T3 (da) | 1997-11-03 |
| TW199863B (sl) | 1993-02-11 |
| BG97168A (bg) | 1993-12-24 |
| CA2085781A1 (en) | 1993-06-22 |
| DE69219574T2 (de) | 1997-11-13 |
| PL297044A1 (en) | 1993-09-06 |
| CN1073603A (zh) | 1993-06-30 |
| HU214056B (en) | 1997-12-29 |
| IL104163A0 (en) | 1993-05-13 |
| ATE152733T1 (de) | 1997-05-15 |
| YU108192A (sh) | 1995-12-04 |
| MA22743A1 (fr) | 1993-07-01 |
| NO924925L (no) | 1993-06-22 |
| GR3024179T3 (en) | 1997-10-31 |
| CA2085781C (en) | 2003-09-23 |
| EP0548825B1 (en) | 1997-05-07 |
| US5670619A (en) | 1997-09-23 |
| CY2116B1 (en) | 2002-04-26 |
| CZ375692A3 (en) | 1993-12-15 |
| HU9204074D0 (en) | 1993-04-28 |
| KR930012034A (ko) | 1993-07-20 |
| HUT63336A (en) | 1993-08-30 |
| AU3021292A (en) | 1993-06-24 |
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