DK176168B1 - Terapeutisk præparat til behandling af chocktilstande ved perfusion - Google Patents
Terapeutisk præparat til behandling af chocktilstande ved perfusion Download PDFInfo
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- DK176168B1 DK176168B1 DK199003041A DK304190A DK176168B1 DK 176168 B1 DK176168 B1 DK 176168B1 DK 199003041 A DK199003041 A DK 199003041A DK 304190 A DK304190 A DK 304190A DK 176168 B1 DK176168 B1 DK 176168B1
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- perfusion
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- 230000035939 shock Effects 0.000 title claims description 10
- 238000011282 treatment Methods 0.000 title claims description 8
- 230000010412 perfusion Effects 0.000 title claims description 7
- 230000001225 therapeutic effect Effects 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims description 22
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical group CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 18
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 13
- 239000002981 blocking agent Substances 0.000 claims description 13
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- 229960000905 indomethacin Drugs 0.000 claims description 9
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 claims description 7
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 2
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- 230000000694 effects Effects 0.000 description 11
- KCWZGJVSDFYRIX-YFKPBYRVSA-N N(gamma)-nitro-L-arginine methyl ester Chemical compound COC(=O)[C@@H](N)CCCN=C(N)N[N+]([O-])=O KCWZGJVSDFYRIX-YFKPBYRVSA-N 0.000 description 9
- NTNWOCRCBQPEKQ-YFKPBYRVSA-N N(omega)-methyl-L-arginine Chemical compound CN=C(N)NCCC[C@H](N)C(O)=O NTNWOCRCBQPEKQ-YFKPBYRVSA-N 0.000 description 7
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- UYZFAUAYFLEHRC-UHFFFAOYSA-N NG-iminoethyl-L-ornithine Natural products CC(N)=NCCCC(N)C(O)=O UYZFAUAYFLEHRC-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
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- 239000004475 Arginine Substances 0.000 description 1
- 206010018873 Haemoconcentration Diseases 0.000 description 1
- 125000002059 L-arginyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
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- NTWVQPHTOUKMDI-YFKPBYRVSA-N N-Methyl-arginine Chemical compound CN[C@H](C(O)=O)CCCN=C(N)N NTWVQPHTOUKMDI-YFKPBYRVSA-N 0.000 description 1
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- 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
-
- 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
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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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Toxicology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Polyurethanes Or Polyureas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
DK 176168 B1
Den foreliggende opfindelse angår nye blokeringsmidler af endothelin-afledt relaksationsfaktor (EDRF) til behandling af forskellige choktilstande, såsom f.eks. stress, septisk chok eller traumatisk chok.
5 Sepsis og endotoxæmi er stadig hovedoversagerne til død i intensiv kirurgiske afsnit til trods for anvendelsen af store mængder specifikke antibiotika, omhyggelig overvågning og operative indgreb. Ikke-overlevende patienter har tendens til en lavere perifer vaskulær modstand, der er beskrevet som "ubehandelig hypotension". Faktisk udviser patienter en dyb vasodilatation 10 især i den præterminale fase, og de dør af perifer vaskulær svigt frem for af cadial svigt. Endvidere er den vedvarende vasodilatation hos disse patienter kun midlertidigt responderende på indsprøjtede catecholaminer eller andre vasokonstriktionsmidler, og den kan sædvanligvis ikke genetableres på grund af en "vaskulær hyporesponsivitet", som er hovedfaktoren, der bidra-15 ger til dødelighedden.
Den foreliggende opfindelsen angår behandlingen af vaskulær hyporesponsivitet i forskellige choktilstande, såsom sepsis, endotoxæmi og andre sygdomme, der fører til vedvarende og dyb systemisk vasodilatation. Behandlin-20 gen omfatter indgift af en effektiv mængde blokeringsmiddel mod effekten eller funktionen af endothelin-afledt relaksationsfaktor (EDRF)- eller nitro-genoxid-lignende faktor.
Det har ifølge opfindelsen vist sig, at blokeringsmidler mod effekten eller 25 dannelsen af EDRF, f.eks. derivater af L-arginin såsom L-N-monomethylarginin eller L-NMMA-L-iminoethylomithin eller L-NIO- og L-nitroarginin-methylester eller L-NAME, er i stand til at genetablere det undertrykte respons på catecholaminer og til effektivt at inhibere vaskulær hypo-reaktivitet.
Disse derivater er L-isomere af forbindelserne med den følgende formel: 30 DK 176168 B1 2
R^N NH
Z \\ / C-NH-(CH~)_-CH / 05 \ R3 COORj^ 5 hvori Ri er H, CH3 eller C2H5, R2 er H eller N02, og 10 R3 er NH2, NHCH3, NHC2H5, CH3 eller C2H5 sammen med et cyclooxygenase-blokeringsmiddel, forudsat at Ri og R2 ikke begge kan være H.
15
Opfindelsen angår i overensstemmelse hermed terapeutiske præparater indeholdende en effektiv mængde af mindst én af de ovennævnte forbindelser sammen med en forligelig bærer og/eller opløsningsmidler til indgift ved injektion.
20
Den kendte teknik kan illustreres ved EP patentansøgning nr. 86117895.2 dateret 22. december 1986, som beskriver cytoprotektive midler og citerer (D) N-methylarginin. Det skal imidlertid bemærkes, at denne forbindelse er unddraget enhver aktivitet inden for området af den foreliggende opfindelse, 25 og at præparaterne ifølge den foreliggende opfindelse ikke udviser nogen cytoprotektiv virkning.
WO 91/04024 omtaler en metode til profylakse eller behandling af systemisk hypotension, hvorved man indgiver en terapeutisk effektiv mængde af en NG-30 substitueret eller NG,NG-disubstitueret arginin.
3 DK 176168 B1 GB patentansøgning, publiceret under GB 2 066 073 A, omtaler farmaceutiske sammensætninger til brug ved beskyttelse mod f.eks. choktilstande, hvor den aktive bestanddel i sammensætningen er en ester af en L-arginin med en alifatisk alkohol.
5 FR patentansøgning, publiceret under FR 2 231 386, omtaler anvendelsen af visse aminosyrer og aminosyrederivater til forebyggelse af skader på fordøjelsessystemet, forårsaget af antiinflammatoriske midler, såsom aspirin, hvor aminosyre eller aminosyrederivat indgives sammen med det antiinflammato-10 riske middel.
Præparaterne ifølge den foreliggende opfindelse adskiller sig fra de præparater, som er kendte fra WO 91/04024 og GB 2 066 073 A, ved at præparaterne ifølge opfindelsen udover den aktive arginin-forbindelse indeholder et 15 cyclooxygenase-blokeringsmiddel.
Præparaterne adskiller sig endvidere fra de præparater, som er kendte fra FR 2 231 386, ved at der er valgt et andet arginin-derivat, og at der med præparaterne ifølge opfindelsen opnås en overraskende virkning i forhold til 20 den virkning, som opnås med præparaterne ifølge FR 2 231 386.
Til eksperimentel demonstration har et stort antal beviser tidligere vist, at dyremodeller for chok in vivo og in vitro efterligner den menneskelige vaskulæ-re hyporesponsivitet over for pressor-neurotransmittere eller hormoner, Wich-25 terman, K.A., Baue, A.E., Chaudry, T.H., "Sepsis and septic shok. A review of laboratory models and a proposal", J. of Surgical Res. 29, 189-201, 1980 og Parrat, J.R. "Alteration in vascular reactivity in sepsis and endotoxemia".
In : Vincent J.L. (Ed.) "Update in intensive care and emergency medicine", Springer Vol. 8, 299-308, 1989. Denne unormal vaskulære responsivitet og 30 effekten af blokeringsmidler mod EDRF kan udmærket demonstreres i vasku-lært væv, der er fjernet fra dyr i chok.
4 DK 176168 B1
For præparaterne ifølge opfindelsen blev dette sandsynliggjort ved følgende eksperimenter: 5 Sprague Dawley rotter (220-330 g) modtog en 10 mg/kg ip injektion af Escherichia Coli-endotoxin (0114B4 Sigma). Efter 3 timer blev rotterne aflivet ved cervicalt dislokation og thoracal aorta blev fjernet og renset fra det omgivne væv. 2 mm brede ringe blev ophængt under en spænding på 2 g ved 37 °C i et organbad indeholdende 10 ml Krebs-Henseleits fysiologiske opløs-10 ning og gennemboblet med 95% 02/5% CO2. Kontraktile respons blev målt ved anvendelse af kraft-forskydningstransducere, Auguet M., Delaflotte S., P.E. Chabrier, P. Braquet, "Comparative effects of endotelin and phorbol 12-13 dibutyrate in rat aorta". Life Sci. 45, 21,2051-2059, 1989.
15 I visse eksperimenter blev endothelet svagt brudt (-E). Phenylephrin (PE)-induceret kontraktion blev med tiden stabil for kontrolringe fra dyr, der modtog saltopløsning (0,9% NaCI) med (E+) eller uden (E-) endothel. Arginin-derivatet (10, 30 eller 100 pM) havde ingen signifikant virkning per se.
20 Omvendt viste ringe fra dyr, der var behandlet med endotoxin, til trods for en tilsvarende kontraktil effekt over for PE, et tab i tonicitet inden for den tid, der betegnes som vaskulær hyporeaktivitet. Dette fænomen blev forstærket ved intakt endothel (E+). Forbindelserne ifølge opfindelsen var ved 10, 30 eller 100 μΜ i stand til at reversere tabet af tonicitet, hvilket viser, at disse forbin-25 delser kunne inhiberer den vaskulære hyporesponsivitet i præparater med eller uden endothel.
Virkningen af præparaterne ifølge opfindelsen var specifik over for inhiberin-gen af EDRF-dannelse, hvorimod L-arginin, det naturlige forstadium af nitro-30 genoxid, forstærkede tabet af tonicitet i endotoxin-behandlede præparater.
5 DK 176168 B1 I nogle eksperimenter, blev præparaterne ifølge opfindelsen indført i et bad 105 minutter efter PE, når vævet havde fuldendt dets tonicitet. Under disse betingelser var præparaterne ifølge opfindelsen alene i stand til helbredende og fuldstændigt at reetablere kontraktionen og derfor bidrage indgående til 5 den vaskulære hyporesponsivitet over for vasokonstriktive midler under chok.
Det har ligeledes vist sig, at virkningen af præparaterne ifølge opfindelsen kan forøges stærkt, når de forekommer sammen med blokeringsmidler for cyclooxygenase såsom aspirin® og indomethacin®. Dette var påvist ved det 10 følgende in vivo-forsøg.
Han-Sprague Dawley rotter (280-320 g) fik udtaget rygmarv og blev inddryppet kontinuert med endotoxin (EDTX, Escherichia Coli-lipopolysaccharid Olll: B4, 300 pg/kg/h) i 60 minutter. Dette resulterede i en systemisk hypotension 15 (formindskelse af DBP, det diastoliske blodtryk), med 40%, en vaskulær hy-poreaktivitet over for stimulation af pressor-midler ledsaget af hæmokon- centration og leukocyt-mangel. Den vaskulære reaktivitet blev målt ved dannelsen af dosis-responskurver over for methoxamin (en αι-agonist) på en kumulativ måde og ved beregning af EDm (effektiv dosis ved 50%). ED5o-20 værdierne for methoxamin var 79 + 9 pg/kg og 278 ± 34 pg/kg for kontrol og EDTX-behandlede rotter (n = 24 dyr). Dyrene blev tildryppet lægemidlerne i 60 minutter. Antallet af rotter i hver gruppe var 5 eller 6. Resultaterne er vist i den følgende tabel. 60 minutters perfusion af endotoxin-lipopolysaccharid (300 pg/kg/h) til udmarvede rotter førte til hypotension og hæmmede den 25 vaskulære reaktivitet hos pressor-midler, således som det observeres ved septisk og endotoxinisk chok hos mennesker. Denne vaskulære hyporeaktivi-tet kan blive inhiberet på en dosis-afhængig måde af blokeringsmidler mod EDRF såsom L-NMMA, L-NAME eller L-NIO, hvilket bekræftes af in vitro-resultater. Deres effekt på blodtrykket er imidlertid mindre markeret. Forenin-30 gen af blokeringsmidler mod cyclooxygenase (Aspirin®, Indomethacin®) og blokeringsmidler mod EDRF resulterer i en stærkt signifikant synergistisk pro- 6 DK 176168 B1 tektiv virkning ved både vaskulær hyperaktivitet og ved formindskelse af blodtryk, der er induceret ved chok.
Det skal bemærkes, at når begge slags forbindelser er sammen, er den re-5 suiterende aktivitet langt mere betydelig end den tilsvarende aktivitet ved blot addition af aktiviteterne fra begge komponenter.
TOXICITET
10 Et studium af akut toxicitet for præparaterne ifølge opfindelsen har været udført på rotter og mus, men ingen døde blev registreret ved den maksimale indgivelige dosis.
DOSOLOGI
15
Til behandlingen af chok omfatter den sædvanlige dosologi indgift ved perfusion af 10 til 100 mg/h af det udvalgte præparat ifølge opfindelsen. Varigheden af behandlingen skal bestemmes i hvert tilfælde i forhold til en tilstrækkelig bedring hos patienten. Præparatet ifølge opfindelsen indeholder for 1 ti-20 mes perfusion fra 10 til 100 mg af den udvalgte forbindelse sammen med fra 0,1 til 1 mg blokeringsmiddel, hvis indomethacin® benyttes, eller fra 2 til 200 mg, hvis aspirin® benyttes, eller de tilsvarende mængder af andre blokeringsmidler mod cyclooxygenase.
7 DK 176168 B1^^
Vaskulær reaktivitet Dosis (methoxamin) (mg/kg/h) ED5Q (ug/kg) ( Kontrol 79+9 5 ------ EDTX-behandlede dyr 278 + 34 L-NMMA 12,5 246 + 31 L-NMMA 50 189 + 15 L-NMMA 100 130 + 8 10 L-NAME 10 238 + 26 L-NAME 30 212 + 11 L-NAME 100 105 + 7 L-NIO 50 200 + 10 L-NIO 400 138 + 12 15 ASPIRIN® 3,75 248 + 24 ASPIRIN 150 136 + 29 ASPIRIN 300 107 + 10 INDOMETHACIN® 0,5 254 + 22 INDOMETHACIN 20 128 + 16 ASPIRIN 3,75 20 + L-NMMA 50 76+15 ASPIRIN 3,75 + L-NAME 30 79 + 12 ASPIRIN 150 + L-NMMA 50 58+5 25 --------:-—- ASPIRIN 150 + L-NAME 30 62+4 INDOMETHACIN 0,5 + L-NMMA 50 80+8 INDOMETHACIN 0,5 30 + L-NAME 30 74 +7 35 .
Claims (4)
1. Terapeutisk præparat til behandling af choktilstande ved perfusion, kendetegnet ved, at det som en aktiv ingrediens omfatter en L-isomer af en i 5 forbindelse med formlen I: » R0N NH- 2 \\ / ,Λ C-NH-(CH_)^-CH 10 / 2 3 \ r3 coor1 hvori Ri er H, CH3 eller C2H5,
15 R2 er H eller NO2, og R3 er NH2, NHCH3i NHC2H5, CH3 eller C2H5 sammen med et cyclooxygenase-blokeringsmiddel, 20 forudsat at R1 og R2 ikke begge kan være H.
2. Terapeutisk præparat ifølge krav 1, hvori cyclooxygenase-blokeringsmidlet er valgt blandt indomethacin og acetylsalicylsyre. 25
3. Præparat ifølge krav 2, kendetegnet ved, at det som en effektiv mængde til en times perfusion indeholder fra 10 til 100 mg af en forbindelse med formlen I og 0,1 -1 mg indomethacin. DK 176168 B1
4. Præparat ifølge krav 2, kendetegnet ved, at det som den effektive mængde til en times perfusion indeholder fra 10 til 100 mg af den udvalgte forbindelse sammen med fra 2 til 200 mg acetylsalicylsyre. #
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB8929076 | 1989-12-22 | ||
GB898929076A GB8929076D0 (en) | 1989-12-22 | 1989-12-22 | Treatment of shock by blocking agents of edrf effect or formation |
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DK304190D0 DK304190D0 (da) | 1990-12-21 |
DK304190A DK304190A (da) | 1991-06-23 |
DK176168B1 true DK176168B1 (da) | 2006-11-13 |
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DK199003041A DK176168B1 (da) | 1989-12-22 | 1990-12-21 | Terapeutisk præparat til behandling af chocktilstande ved perfusion |
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US (1) | US5081148A (da) |
JP (1) | JP2706578B2 (da) |
KR (1) | KR950005866B1 (da) |
AT (1) | AT403122B (da) |
AU (1) | AU629777B2 (da) |
BE (1) | BE1005531A5 (da) |
CA (1) | CA2032904C (da) |
CH (1) | CH681692A5 (da) |
DE (1) | DE4041283C2 (da) |
DK (1) | DK176168B1 (da) |
FR (1) | FR2656220B1 (da) |
GB (2) | GB8929076D0 (da) |
HK (1) | HK134693A (da) |
IE (1) | IE64403B1 (da) |
IT (1) | IT1246511B (da) |
LU (1) | LU87867A1 (da) |
MY (1) | MY105328A (da) |
NL (1) | NL194717C (da) |
OA (1) | OA09337A (da) |
SE (1) | SE504922C2 (da) |
ZA (1) | ZA9010004B (da) |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE468881B (sv) * | 1991-01-09 | 1993-04-05 | Kabi Pharmacia Ab | Anvaendning av vissa foereningar foer framstaellning av laekemedel foer behandling av endotoxininducerade effekter samt saett att avlaegsna endotoxiner ur diverse loesningar |
GB9127376D0 (en) * | 1991-12-24 | 1992-02-19 | Wellcome Found | Amidino derivatives |
GB9200114D0 (en) * | 1992-01-04 | 1992-02-26 | Scras | Dual inhibitors of no synthase and cyclooxygenase |
US5385940A (en) * | 1992-11-05 | 1995-01-31 | The General Hospital Corporation | Treatment of stroke with nitric-oxide releasing compounds |
US5585402A (en) * | 1992-12-23 | 1996-12-17 | Glaxo Wellcome Inc. | Nitric oxide synthase inhibitors |
US5436270A (en) * | 1993-04-07 | 1995-07-25 | National Science Council | Method for protecting against endotoxin-induced shock |
GB9312204D0 (en) * | 1993-06-14 | 1993-07-28 | Zeneca Ltd | Therapeutic composition |
GB9312761D0 (en) * | 1993-06-21 | 1993-08-04 | Wellcome Found | Amino acid derivatives |
US6297276B1 (en) | 1993-10-04 | 2001-10-02 | Glaxosmithkline | Substituted urea and isothiourea derivatives as no synthase inhibitors |
US6225305B1 (en) | 1993-10-04 | 2001-05-01 | Glaxo Wellcome Inc. | Substituted urea and isothiorea derivatives as no synthase inhibitors |
US6090846A (en) * | 1994-06-01 | 2000-07-18 | Glaxo Wellcome Inc. | Substituted urea and isothiourea derivatives as no synthase inhibitors |
CN1077886C (zh) * | 1993-10-21 | 2002-01-16 | G·D·瑟尔公司 | 用作一氧化一氮合酶抑制剂的脒基衍生物 |
PT724435E (pt) * | 1993-10-21 | 2002-11-29 | Searle & Co | Derivados amidino uteis como inibidores de oxido nitrico sintase |
GB9404400D0 (en) * | 1994-03-07 | 1994-04-20 | Wood Pauline J | Potentiation of bioreductive agents |
DE69518631T2 (de) * | 1994-03-10 | 2001-01-11 | G.D. Searle & Co., Chicago | L-n6-(1-iminoethyl)lysin - derivate und ihre verwendung als no-synthase - inhibitoren |
US5684008A (en) * | 1994-11-09 | 1997-11-04 | G. D. Searle & Co. | Aminotetrazole derivatives useful as nitric oxide synthase inhibitors |
FR2727111B1 (fr) * | 1994-11-21 | 1997-01-17 | Hoechst Lab | Nouveaux analogues soufres d'aminoacides, leur procede de preparation et leurs applications comme medicaments |
JPH10510540A (ja) * | 1994-12-12 | 1998-10-13 | オメロス メディカル システムズ,インコーポレーテッド | 灌注用溶液並びに疼痛、炎症及びけいれんの抑制法 |
KR100517210B1 (ko) * | 1994-12-12 | 2006-06-07 | 오메로스 코포레이션 | 통증,염증및경련억제용관주용액 |
ATE532530T1 (de) * | 1994-12-12 | 2011-11-15 | Omeros Corp | Bespüllungslösung und deren verwendung zur perioperativen hemmung von schmerzen, entzündungen und/oder spasmen an einer gefässstruktur |
FR2730930B1 (fr) | 1995-02-27 | 1997-04-04 | Oreal | Utilisation d'inhibiteurs de no-synthase pour diminuer l'effet irritant cutane de produits utilises dans le domaine cosmetique ou pharmaceutique |
GB9504350D0 (en) * | 1995-03-04 | 1995-04-26 | Sod Conseils Rech Applic | Arginine derivatives |
EP0821674B1 (en) * | 1995-04-20 | 2003-08-06 | G.D. SEARLE & CO. | Cyclic amidino agents useful as nitric oxide synthase inhibitors |
US5830917A (en) * | 1995-09-11 | 1998-11-03 | G. D. Searle & Co. | L-N6 -(1-iminoethyl) lysine derivatives useful as nitric oxide synthase inhibitors |
US5981511A (en) * | 1996-03-06 | 1999-11-09 | G.D. Searle & Co. | Hydroxyamidino derivatives useful as nitric oxide synthase inhibitors |
US5945408A (en) * | 1996-03-06 | 1999-08-31 | G.D. Searle & Co. | Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors |
US6369272B1 (en) | 1997-01-13 | 2002-04-09 | Glaxosmithkline | Nitric oxide synthase inhibitors |
US6620848B2 (en) | 1997-01-13 | 2003-09-16 | Smithkline Beecham Corporation | Nitric oxide synthase inhibitors |
US5981556A (en) * | 1997-07-22 | 1999-11-09 | G.D. Searle & Co. | 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors |
GB9811599D0 (en) | 1998-05-30 | 1998-07-29 | Glaxo Group Ltd | Nitric oxide synthase inhibitors |
JP2002517502A (ja) | 1998-06-10 | 2002-06-18 | ジー・ディー・サール・アンド・カンパニー | 複素二環状及び三環状一酸化窒素シンターゼ阻害剤 |
US6344473B1 (en) | 2000-08-07 | 2002-02-05 | G.D. Searle & Co. | Imidazoles useful as nitric oxide synthase inhibitors |
EP1699793A1 (en) | 2003-12-30 | 2006-09-13 | Vasopharm Biotech GmbH | 4-amino-7,8-dihydropteridines, pharmaceutical compositions containing them and their use for the treatment of diseases which are caused by an increased nitric oxide level |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB931921A (en) * | 1960-12-22 | 1963-07-24 | Lab Roques | Therapeutic compositions intended for the treatment of any hepatic malfunctionings |
GB1195612A (en) * | 1967-04-13 | 1970-06-17 | Sumitomo Chemical Co | An Injection |
FR2115060A1 (en) * | 1970-11-26 | 1972-07-07 | Metabio | Freeze-dried acetylsalicylates of lysine and arginine - easily prepd derivs of aspirin |
CA1029660A (en) * | 1973-06-01 | 1978-04-18 | Kyowa Hakko Kogyo Co. | Prevention of gastric lesions |
FR2320759A1 (fr) * | 1975-08-11 | 1977-03-11 | Union Pharma Scient Appl | Solution d'acide acetylsalicylique extemporanee injectable |
IT1127322B (it) * | 1979-12-28 | 1986-05-21 | Italfarmaco Spa | Composizioni farmaceutiche con esaltazione dell'attivita' terapeutica di cortisonici |
IT1127321B (it) * | 1979-12-28 | 1986-05-21 | Italfarmaco Spa | Composizione farmaceutiche aventi specifiche proprieta' terapeutiche nei confronti dell'edema polmonare acuto,di alcuni stati di shock e dell'iperfibrinolisi |
JPS5781409A (en) * | 1980-11-10 | 1982-05-21 | Toko Yakuhin Kogyo Kk | External plaster |
JPS57197211A (en) * | 1981-05-28 | 1982-12-03 | Sumitomo Chem Co Ltd | Useful eye drop composition |
JPS57200361A (en) * | 1981-06-03 | 1982-12-08 | Sumitomo Chem Co Ltd | "indomethacin(r)" pharmaceutical with low irritant action |
JPS6239524A (ja) * | 1985-08-13 | 1987-02-20 | Toko Yakuhin Kogyo Kk | 消炎鎮痛軟膏剤 |
JPH0236570B2 (ja) * | 1985-05-30 | 1990-08-17 | Toko Yakuhin Kogyo Kk | Shoenchintsunankozai |
IT1201511B (it) * | 1985-12-23 | 1989-02-02 | Italfarmaco Spa | Derivati citoprotettivi in patologie a base ischemica,loro preparazione e composizioni che li cntengono |
WO1988006035A1 (en) * | 1987-02-20 | 1988-08-25 | Shriners Hospitals For Crippled Children | Omega-3 fatty acids in traumatic injury treatment |
-
1989
- 1989-12-22 GB GB898929076A patent/GB8929076D0/en active Pending
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1990
- 1990-12-11 NL NL9002720A patent/NL194717C/nl not_active IP Right Cessation
- 1990-12-12 SE SE9003974A patent/SE504922C2/sv not_active IP Right Cessation
- 1990-12-12 ZA ZA9010004A patent/ZA9010004B/xx unknown
- 1990-12-14 BE BE9001200A patent/BE1005531A5/fr not_active Expired - Fee Related
- 1990-12-18 IT IT02241390A patent/IT1246511B/it active IP Right Grant
- 1990-12-19 IE IE459290A patent/IE64403B1/en not_active IP Right Cessation
- 1990-12-19 FR FR9015904A patent/FR2656220B1/fr not_active Expired - Fee Related
- 1990-12-19 US US07/630,273 patent/US5081148A/en not_active Expired - Lifetime
- 1990-12-19 CH CH4034/90A patent/CH681692A5/fr not_active IP Right Cessation
- 1990-12-20 MY MYPI90002223A patent/MY105328A/en unknown
- 1990-12-20 AT AT0260690A patent/AT403122B/de not_active IP Right Cessation
- 1990-12-21 DK DK199003041A patent/DK176168B1/da not_active IP Right Cessation
- 1990-12-21 DE DE4041283A patent/DE4041283C2/de not_active Expired - Fee Related
- 1990-12-21 CA CA002032904A patent/CA2032904C/en not_active Expired - Lifetime
- 1990-12-21 KR KR1019900021355A patent/KR950005866B1/ko not_active IP Right Cessation
- 1990-12-21 OA OA59932A patent/OA09337A/xx unknown
- 1990-12-21 AU AU68376/90A patent/AU629777B2/en not_active Ceased
- 1990-12-21 LU LU87867A patent/LU87867A1/fr unknown
- 1990-12-24 GB GB9028013A patent/GB2240041B/en not_active Expired - Lifetime
- 1990-12-25 JP JP2419113A patent/JP2706578B2/ja not_active Expired - Lifetime
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