NO852272L - Hjerteventil. - Google Patents

Hjerteventil. Download PDF

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Publication number
NO852272L
NO852272L NO852272A NO852272A NO852272L NO 852272 L NO852272 L NO 852272L NO 852272 A NO852272 A NO 852272A NO 852272 A NO852272 A NO 852272A NO 852272 L NO852272 L NO 852272L
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Norway
Prior art keywords
valve prosthesis
valve
accordance
main part
flap
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NO852272A
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English (en)
Inventor
Shlomo Gabbay
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Shelhigh Inc
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Publication of NO852272L publication Critical patent/NO852272L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2220/0025—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements
    • A61F2220/0075—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements sutured, ligatured or stitched, retained or tied with a rope, string, thread, wire or cable
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/90—Stent for heart valve

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Prostheses (AREA)
  • External Artificial Organs (AREA)
  • Materials For Medical Uses (AREA)

Description

Oppfinnelsen vedrører en ventilprotese for regulering av blodstrøm, mer bestemt, en hjerteventilprotese.
Innenfor området hjerteventiler har konvensjonelle ventilproteser problemer med turbulens som begrenser blodstrømmen og kan forårsake blodpropper, irritasjon eller skjelving i hjerteveggene, eller kneppende lyder fra ventilen, noe som kan være ukomfortabelt eller forstyrrende for brukeren. Fra søkerens US patentskrift nr. 4 275 469 ert det kjent en forbedret hjerteventilprotese som består av en åpen trådramme eller rørmembran som har en fleksibel innløpsende som er festet til et hjertets ringåpning og en utløpsende som har en langstrakt, enkel klaff eller flik innrettet til å bevege seg fram og tilbake i forhold til membranveggen for å åpne og lukke ventilen ved utløpsenden. Fra søkerens US patentsøknad nr 841791 innlevert 13. oktober 1977, er det kjent en forbedret utførelse av en dobbeltfliket hjerteventil som fastholdes av en halvfleksibel støttering som tilnærmet simulerer en naturlig hjerteventil.
Imidlertid er disse og andre kjente typer hjerteventiler beheftet med problem at områder som utgjøres av frilagt syntetisk materiale, slik som sømringen hvormed ventilen er festet til hjerteveggen, forblir utildekket og derved ikke blir endoteliasert, dvs. inhyllet i biologisk vev. En grunn til dette er fenomen er at syntetisk materiale har en tendens til å avvise tildekning av levende vev, dvs. epitelium (overflatevev), eller har samleflater som utgjør trombogene soner. Det har også vist seg at til og med biologisk vev, f.eks. perikardium (hjertepose), som har en ru overflate på den ene siden som vanligvis vender innover mot blodstrømsområdet i ventilen, medfører en fare for at soner på den ru overflaten kan ha tendens til å forårsake dannelse av blodpropp som kan føre til trombo-embolisme. Et annet problem er at det kan oppstå forholdsvis rnange tilfeller av infeksjoner (endokarditis) p.g.a. bakterievekst eller opphopning av vekstdannelser i slike oppsamlings-soner. Spesielt har det vist seg at bruk av perikardialt vev, som har en ru side vendt mot blodstrømsområdet, medfører en fare for infeksjoner eller trombose p.g.a oppsamling av blodplater eller av normal vevvekst på,den ru overflate.
Ifølge oppfinnelsen er det et generelt formål å fremskaffe en hjerteventilprotese som er konstruert slik og fremstilt av egnet materiale, slik at faren for trombose blir redusert. Et ytterligere formål er å fremskaffe en hjerteventil som gir redusert fare for infeksjoner, og som er fleksibel, holdbar og som kan funksjonere feilfritt over lengre tid.
Hjerteventilprotesen ifølge oppfinnelsen er utstyrt med en bærende hoveddel eller ramme med fleksibel og holdbar konstruksjon som er dekket av biologisk vev, f.eks. perikardialt materiale som er ombrettet slik at det bare er den glatte overflaten som vender utad mot blodstrømsområdet.
Rammen er fortrinnsvis sylinderformet og har et bortskåret parti ved sin utløpsende som er utformet til å oppta en ventil-klaff eller -spiss hensiktsmessig i den åpnede eller lukkete stilling. Kanten av dens bortskårne parti er fortrinnsvis forsynt med en remse av silikon, et eller flere lag perikardium eller annet støttemateriale for å redusere muligheten for opptredende av revner eller brudd langs kanten. Spissen som er laget av dobbeltbrettet biologisk vev er fastsydd til den perikardiumdekkete rammen langs kanten på det bortskårne parti. Spissen og det bortskårne parti er dimensjonert slik at de sikrer en fullstendig stengning av blodstrømmen i den lukkete stilling. En sømring er anordnet ved ventilens innløpsende og er laget av perikardialt eller annet biologisk vev eller av dacronmateriale impregnert med kollagen eller annet biologisk akseptabelt materiale .
Ytterligere trekk ved oppfinnelsen vil fremgå av den følgende beskrivelse under henvisning til de medfølgende tegn-inger, hvori: Fig. 1 viser et skjematisk riss av en ramme ifølge en første utførelsesform av oppfinnelsne. Fig. 2 viser et riss av rammen i fig. 1, sett forfra. Fig. 3 viser et riss av rammen i fig. 1, sett fra
siden.
Fig. 4 viser et perspektivriss av rammen, dekket med perikardialt materiale og utstyrt med en sømring ifølge oppfinnelsen. Fig. 5 viser et perspektivriss av en komplett sammen-stilling av hjerteventilprotesen ifølge oppfinnelsen. Fig. 6 viser et snitt av den sammenstilte hjerteventilen i lukket stilling sett fra siden. Fig. 7 viser i et skjematisk riss en foretrukket utforming av rammeprofilen. Fig. 8 viser et nærbilde av de glatte og de ru over-flatene i det perikardiale vev. Fig. 9 viser den sammenstilte hjerteventilen i åpen stilling.
Fig. 10 viser hjerteventilen i lukket stilling.
Fig. 11 viser et perspektivriss av en bærende trådramme ifølge en andre utførelse av oppfinnelsen.
I det etterfølgende vil det bli beskrevet foretrukne utførelsesformer, som kun er ment å illustrere prinsippene ifølge oppfinnelsen, uten derved å begrense disse. På tegningene blir like deler henvist med like henvisningstall.
Under henvisning til fig. 1 er det vist en bærende hoveddel eller ramme 1, som er laget av et fleksibelt materiale, fortrinsvis en plast av f.eks. Delrin- eller Teflonmateriale, og som har en stort sett rett sylindrisk form med vesentlig samme diameter i hele lengdeutstrekningen. Et nedre ringområde 2 utgjør innløpet til ventilen og danner basis for feste av ventilen til en hjertering. En øvre del 3 av rammen 1 omfatter et sylindrisk parti som strekker seg over tilnærmelsesvis halve omkretsen og et bortskåret parti over den resterende del av omkretsen. Det bortskårne parti er avgrenset ved nedadvendende, krumme kanter 4 som ender i en horisontal kant 5 i samme plan som basisen 2. Et avrundet hjørne er utformet der hvor den krumme kanten 4 forbindes med kanten på den øvre del 3, for derved å unngå faren for at vev skal rives istykker. Rammen 1 har mange sømhuller 6 og spalter 7 for å kunne feste et lag av tildekkings-vev til rammen, slik som det ytterligere skal beskrives i det etterfølgende. Spaltene 7 avsluttes med runde huller 7a som fordeler spenningskreftene ved spaltens ender for derved å hindre brudd i platematerialet etter gjentatte bøyninger mens ventilen er i bruk. En støtteremse 4a av silikon, enkle eller dobble remser av perikardium, eller annet ettergivende materiale kan benyttes til å utjvene kurvekanten 4, med den hensikt å unngå rivninger i vevet som er festet dertil.
For å redusere frileggingen av syntetisk overflate mot blodstrømmen og dannelsen av mulige trombogene soner, er rammen dekket med et eller flere lag av biologisk vev, f.eks. perikardialt vev 8, som har en ru side 10 og en glatt side 9 som vist på fig. 8. Det skal henvises til fig. 4 og 5, hvor det perikardiale vev 8 er brettet over rammens bærevegger og er sydd til rammen langs de nedadvendende, krumme kanter 4 ved omkretsen av basisen 2 og gjennom spaltene 7.
En hjerteventilspiss eller -klaff 11 er deretter ved
det bortskårne parti av rammen, ved dens nedre kant lia, fastsydd ved<*N>sømhullene som løper langs rammens nedadvendende krumme kant 4. Klaffen er utformet av biologisk vev, f.eks. perikardium, som har en ru side og en glatt side. Den ru side 10 kan forårsake
ansamlingssoner for bakterier og annen vevvekst som øker risikoen for infeksjoner og som til slutt kan resultere i forkalkninger. Ifølge oppfinnelsen er det perikardiale vev brettet dobbelt, slik at den ru side er vendt innover og bare den glatte side 9 er frilagt mot blodstrømområdet og mot hjerteveggen som er kontakt med ventilens utside. Det dobbeltbrettete perikardium øker vegg-tykkelsen til det dobbelte og er derfor sterkere og øker mot-standen mot utmatting, brudd henholdsvis ventilsvikt. Det kan anvendes lim, f.eks. fibrinlim, til å forbinde de indre overflater til en mer friksjonsfast klaffkonstruksjon. Den øvre del 11b av klaffen 11 løper over den øvre del 3 av rammen. Når ventilen er i funksjon og inntar sin lukkete stilling, vil den øvre del 11b falle innad mot den øvre dels 3 innervegger, som vist i fig. 10, for derved å lukke blodstrømpassasjen gjennom ventilen. I den åpne stillingen vender klaffen 11 tilbake til sin oppadvente stilling, ved at blodstrømmen beveges gjennom ventilen.
Klaffen 11 er fortrinsvis laget av biologisk materiale, f.eks. parikardium fra kveg (membranen rundt et hjerte fra en kalv eller et annet dyr). Perikardiumet er fortrinnsvis behandlet med gluteraldehyd, noe som sikrer at vevet blir inert og ikke gir grunnlag for avvisning ved immunolog respons fra det menneskelige legeme. Behandlingen av perikardiumet foregår i en form, slik at materialet kan gis den valgte krumme fasong til bruk i ventilen, slik som vist i lukket stilling i fig. 10. Materialet er ytterst sterkt og fleksibelt og har en høy elastisitetsmodul, slik at ventilen kontinuerlig kan åpnes og lukkes samtidig som membranen beholder sin opprinnelsige form. Annet biologisk akseptebelt materiale som kan benyttes er duramater, eksempelvis membranen som omgir den menneskelige hjerne eller hjernen hos dyr som gris, sau eller kalv.
Hjerteventilen har også en mansjett eller sømring 12 som strekker seg i omkretsretningen rundt rammens basis 2, og som holdes på plass ved en søm gjennom sømhullene 6, som vist i fig. 6. Fortrinnsvis er sømringen 12 laget av perikardialt vev eller annet biologisk materiale, eller av dacron som er impregnert med kolNlagen eller annet biologisk akseptabelt materiale. Ved materiale bruk av den ovenfor beskrevne ventilkonstruksjonen av perikardium, biologisk vev, eller av biologisk behandlet materiale, oppnår man effektivt en fullstendig aksepterbar biologisk hjerteventil med glatte utadvendende overflater, som reduserer muligheten for at ventilen, når den er festet til hjertet, vil danne ikke-endoteliaserte områder eller vil utvikle trombogeniske områder eller infeksjonsområder.
Under henvisning til fig. 7 er det vist en foretrukken geometrisk profil for rammens krummete kanter 4. På tegningen er det vist rammens langsgående retning langs Y-aksen, og dens tverrgående retning langs X-aksen. Den foretrukne krumming av kanten 4, som antydet med buen A-B, en hovedsakelig elliptisk kurve med senter ved 0, som er det øverste punkt på klaffen 11 som er festet til rammen 1 (vist med skraverte linjer). R angir ellipsens radius mellom punktet 0 og punktet A. L angir den lineære avstand fra punktet A til rammens øvre kant. OD angir rammens ytre diameter og avstanden fra punktet B til rammeveggens kant er vanligvis valgt lik halvparten av den ytre diameter. En spesielt foretrukken geomertisk profil for de krummete kanter 4 er gitt ved formelen: og
Med en slik profil er klaffen 11, når den er sydd fast til den krummete kant 4, anordnet på passende måte til å falle sammen med rammens innervegg for å lukke ventilen. I fig 9 og 10 er det vist en sammenstilt ventil i åpen og lukket stilling.
Ventilprotesen ifølge oppfinnelsen er følgelig gitt en holdbar konstruksjon med glatt overflate, med spisser av dobbel-brettet biologisk vev og med en sømring av biologisk eller biolo gisk behandlet materiale. En. slik fullstendig biologisk og over-flateglatt ventilkonstruksjon reduserer muligheten for infeksjoner ved bakterievekst eller unormal vevvekst som oppstår på ru overflate eller på steder som ikke er dekket av epitelium. Den angitte profil for det bortskårne parti av rammen gir en mer korrekt dimensjonering for lukking av ventilen ved hjelp av klaffen. Selv om ventilprotesen er spesielt hensiktsmessig som en hjerteventil, kan den også brukes som arterie- eller vene-ventil.
Den beskrevne ventilprotese, hvori det benyttes en enkelt lags spiss, er blitt testet og funnet å være mer holdbar enn andre, alminnelig kjente biologiske ventiler. Ved mekaniske belastningstester, hvor testene blir utført med omtrent ti ganger større belastning enn ved normal bruk, varte foreliggende ventil i langt mer enn 200 millioner sykluser. Ved dyreforsøk har den foreliggende ventil vist minimalt antall tilfeller av infeksjoner eller tromboser. Ved en ventil ifølge oppfinnelsen, hvor det benyttes dobbeltbrettet spiss, kan man oppnå en lengre holdbarhet i tillegg til at man reduserer trombosefaren.
Et annet særlig fordelaktig trekk ved oppfinnelsen er den forbedrete metode for lagring av ventilen i alkohol, eller annen antiseptisk løsning som ikke er skadelig for det menneskelige legeme forut for ventilens anbringelse i legemet. Det er vanlig å lagre ventilprotesen i glutaraldehyd, noe som krever omtrent 5 timer til rengjøring av ventilen forut for anbringelse, idet glutaraldehyd kan forårsake forkalkning ved opptakelse av ventilen i legemet. Ved å lagre ventilen i alkohol, kan den ganske enkelt rengjøres med vann like forut for anbringelsen.
Ifølge en andre utførelse av oppfinnelsen benyttes det for ventilen en åpen trådramme, som vist i US patent nr. 4 275 469, istedenfor som vist i fig. 1. I fig. 11 er det vist en ventilbæredel 21 med en avrundet trådramme 22 utstyrt med krummete lister 24 og en øvre rand 23 som spenner over halve omkretsen, samt sidespenner 25 som tilsammen utgjør en en inte-grerende del. Rammen 22 er festet til nedre bånd 26 utstyrt med sømhull 27. Perikardialt materiale er brettet over rammen 22, med sin glatte side vendt utad og festet til båndene 26, idet en mansjett er sydd på plass langs omkretsen av båndet til dannelse av en ventilhoveddel-konstruksjon tilsvarende den som er vist i og beskrevet under henvisning til fig. 4. Perikardialt materiale er deretter brettet dobbelt til dannelse av den overflateglatte spiss som deretter er festet til ventilhoveddelen langs de krummete lister 24 og bånd 26. Listenes 24 krumming er fortrinnsvis stort sett ellipseformet med dimensjoner tilsvarende de som angitt ovenfor, for derved å gi optimal utforming av spissen ved lukking av ventilhoveddelen.
Selv om bare disse spesielle utførelser ifølge oppfinnelsen er blitt beskrevet, finnes det mange andre variasjoner og modifikasjoner av prinsippene ifølge oppfinnelsen, slik det vil være nærliggende for en fagmann på området, innbefattet erstat-ninger av egnete materialer, egnete deler, henholdsvis egnete fremgangsmåter. Alle slike variasjoner og modifiksjoner er ment å falle innenfor oppfinnelsens rammer slik de er definert i de etterfølgende krav.

Claims (16)

  1. En ventilprotese karakterisert ved at den omfatter en bærende hoveddel som har hovedsakelig sylindrisk form og som har en nedre basisdel som løper langs hoveddelens omkrets, en øvre del som løper over en del av nevnte omkrets og et bortskåret parti som er avgrenset av den resterende del av omkretsen idet hoveddelen har kanter som løper bueformet langs det bortskårne parti fra den øvre del til basisdelen, en rekke av sømhuller som er utformet i hoveddelen, et dekke av biologisk vev som er festet til hoveddelen via.^ sømhullene og som har glatte utadvendende overflater, en fleksibel klaff som er av biologisk vev, til åpning og lukking av ventilen, og som har en nedre del som er festet til den krumme kanten og til basisdelen, og som har en øvre del som løper over den øvre del av hoveddelen, idet klaffen og det bortskårne parti av hoveddelen er slik dimensjonert at klaffen kan falle innad til lukket stilling mot hoveddelens innervegg for lukking av ventilen.
  2. 2. Ventilprotese i samsvar med krav 1, karakterisert ved at klaffen er laget av perikardialt vev som er dobbeltbrettet, slik at dens ru side vender innover og bare dens glatte side er frilagt.
  3. 3. Ventilprotese i samsvar med krav 1, karakterisert ved at en sømring som strekker seg langs basisdelens omkrets er laget av perikardialt ved, biologisk vev, eller dacron-duk impregnert med kollagent materiale.
  4. 4. Ventilprotese i samsvar med krav 1, karakterisert ved at klaffen er utformet av duramater.
  5. 5. Ventilprotese i samsvar med krav 1, karakterisert ved at den krummete kanten har t elliptisk tverrsnitt definert av en ellipse med formelen:
    hvor R er lengden av klaffen regnet fra dens øvre del til dens nedre del ved hoveddelens basis, L er lengden fra skjæringspunktet mellom nevnte basis og den krumme kant av hoveddelens øvre del, OD er den sylindriske hoveddelens ytre diameter, X er ellipsens koordinat i tverretningen av hoveddelens langsgående krumme kant, og Y er ellipsens koordinat i lengderetningen av hoveddelens langsgående kant.
  6. 6. Ventilprotese i samsvar med krav 1, karakterisert ved at dekket er laget av perikardialt vev som er brettet over hoveddelens øvre del og festet til denne via sømhullene.
  7. 7. Ventilprotese i samsvar med krav 1, karakterisert ved at hoveddelene er en sylindrisk formet ramme laget av syntetisk materiale.
  8. 8. Ventilprotese i samsvar med krav 1, karakterisert ved at hoveddelen dannes av en åpen trådramme omfattende den øvre del , et bortskåret parti og krummete kanter samt et nedre bånd som er festet til trådrammen og utstyrt med en rekke sømhuller.
  9. 9. Ventilprotese i samsvar med krav 1, karakter- isertved en forsterkningsremse som er festet iallefall til den bærende hoveddels krummete kanter.
  10. 10. Ventilprotese i samsvar med krav 9, karakterisert ved at forsterkningsremsen er laget av silikon.
  11. 11. Ventilprotese i samsvar med krav 9, karakterisert ved at forsterkningsremsen er laget av et lag av perikardialt vev.
  12. 12. Ventilprotese i samsvar med krav 2, karakterisert ved at den ru side av det dobbeltbrettete perikardiale vev er sammenfestet med lim.
  13. 13. Ventilprotese i samsvar med krav 1, karakterisert ved i den bærende hoveddel utformete, tverrgående søm-spalter.
  14. 14. Ventilprotese i samsvar med krav 13, karakterisert ved at spaltene er avsluttet i sirkulære huller ved mot-stående ender for å redusere faren for mekaniske brudd ved spalteendene.
  15. 15. Ventilprotese i samsvar med krav 6, karakterisert ved at dekket omfatter flere lag av perikardialt vev.
  16. 16. Fremgangsmåte til bruk av en ventilprotese laget av biologisk materiale, karakterisert ved at ventilen lagres i alkohol og rengjøres umiddelbart før innsetting.
NO852272A 1984-12-07 1985-06-06 Hjerteventil. NO852272L (no)

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US06/679,261 US4759758A (en) 1984-12-07 1984-12-07 Prosthetic heart valve

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NO852272L true NO852272L (no) 1986-06-09

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US (1) US4759758A (no)
EP (1) EP0183904B1 (no)
JP (1) JPS61137556A (no)
AT (1) ATE46815T1 (no)
AU (1) AU582360B2 (no)
CA (1) CA1255052A (no)
DE (1) DE3573371D1 (no)
DK (1) DK565985A (no)
ES (1) ES8608308A1 (no)
IL (1) IL75301A (no)
NO (1) NO852272L (no)
PT (1) PT80671B (no)
ZA (1) ZA853590B (no)

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DK565985A (da) 1986-06-08
AU4246785A (en) 1986-06-12
DK565985D0 (da) 1985-12-06
ES8608308A1 (es) 1986-07-16
CA1255052A (en) 1989-06-06
ES544301A0 (es) 1986-07-16
EP0183904A2 (en) 1986-06-11
DE3573371D1 (en) 1989-11-09
ZA853590B (en) 1985-12-24
IL75301A0 (en) 1985-09-29
EP0183904A3 (en) 1987-01-21
ATE46815T1 (de) 1989-10-15
AU582360B2 (en) 1989-03-23
PT80671A (en) 1985-07-01
US4759758A (en) 1988-07-26
EP0183904B1 (en) 1989-10-04
PT80671B (en) 1987-02-06
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JPS61137556A (ja) 1986-06-25

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