DK160807B - IMMUNO MODULATIVE MEDICINALS OF BIOLOGICAL ORIGIN AND METHOD OF PRODUCING THEREOF - Google Patents
IMMUNO MODULATIVE MEDICINALS OF BIOLOGICAL ORIGIN AND METHOD OF PRODUCING THEREOF Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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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
Abstract
Description
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Den foreliggende opfindelse angår et immunomodulerende lægemiddel af biologisk oprindelse, hvis aktive bestanddel består af lyseprodukter eller en fraktion af sådanne produkter fra bakterier, der er lyseret ved hjælp af bak-5 teriofager samt fremgangsmåde til fremstilling deraf.The present invention relates to an immunomodulating drug of biological origin, the active ingredient of which consists of lysis products or a fraction of such products from bacteria lysed by bacteriophages and their method of preparation.
Man kender talrige præparater, som modulerer immunresponset ved hjælp af fraktioner eller ekstrakter af lyserede mikroorganismer. Man kan især nævne sådanne pro-10 dukter, som er omtalt i de franske patentskrifter nr.Numerous compositions are known which modulate the immune response by fractions or extracts of lysed microorganisms. Particular mention may be made of such products which are disclosed in the French Patent Specification no.
2 374 042, 2 396 018 og 2 426 470.2 374 042, 2 396 018 and 2 426 470.
Disse lysater eller ekstrakter er i almindelighed opnået ved fysiske, kemiske og mindre hyppigt ved enzymatiske 15 fremgangsmåder. Størstedelen af disse præparater har en vis immunomodulerende aktivitet, som er påvist hos dyr, men de terapeutiske virkninger over for mennesker er stadig genstand for talrige undersøgelser (Immuno-pharmacologie Clinique. Réalités et Perspectives, G.These lysates or extracts are generally obtained by physical, chemical and less frequently by enzymatic procedures. The majority of these preparations have some immunomodulatory activity detected in animals, but the therapeutic effects on humans are still the subject of numerous studies (Immuno-pharmacologie Clinique. Réalités et Perspectives, G.
20 RENOUX. Pharmacologie et thérapeutique. R.P. 1982, 32, 41-42).20 RENOUX. Pharmacology and Therapeutics. R.P. 1982, 32, 41-42).
Det er således vigtigt at prøve at finde lægemidler, som kan tilbyde såvel læger som dyrlæger et våben, som kan 25 anvendes hver gang, det drejer sig om at retablere eller at forstærke immunforsvaret.Thus, it is important to try to find drugs that can offer both doctors and veterinarians a weapon that can be used every time it is about recovering or strengthening the immune system.
Artikler af Y. Centifanto i Proc. Soc. Exptl. Biol. og Med. vol. 120 nr. 3, 607-11, 1965, beskriver et anti- 30 viralt, terapeutisk middel, der er fremstillet ud fra en ekstrakt af inficerede Escherichia coli (Phagicin), og P.Articles by Y. Centifanto in Proc. Soc. Exp. Biol. and with. Vol. 120 No. 3, 607-11, 1965, discloses an antiviral therapeutic agent prepared from an extract of infected Escherichia coli (Phagicin) and P.
Actor, Infection and Immunity, vol. 6, nr. 5, nov. 1972, p. 886-888 har undersøgt den beskyttende virkning af en ribonucleinsyre, der er opnået ved bakteriofaginfektion 35 af Escherichia coli.Actor, Infection and Immunity, Vol. 6, No. 5, Nov. 1972, pp. 886-888 have investigated the protective effect of a ribonucleic acid obtained by bacteriophage infection 35 of Escherichia coli.
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Man har nu fundet en hidtil ukendt fremstillingsmåde, hvor der anvendes bakteriofager. Bakteriofager udgør in vitro et fremragende redskab til lyse af bakterier, hvorfor anvendelsen deraf til fremstilling af immunomodule-5 rende præparater har vist sig effektiv med forskellige arter og typer af bakterier. Denne teknik til lyse af bakterier ved hjælp af bakteriofager er uden begrænsning med hensyn til bakteriearten eller bakterietypen. Denne fremgangsmåde gør det muligt at opnå lægemidler, der er 10 bemærkelsesværdige ved deres evne til modulering af immunsystemet, og de er fremstillet ud fra flere bakterier eller en blanding af sådanne bakterier. Disse lægemidler har især en evne til at inducere interferoner.A novel method of using bacteriophages has now been found. Bacteriophages constitute an excellent tool for the lysis of bacteria in vitro, and their use in the preparation of immunomodulatory preparations has proved effective with various species and types of bacteria. This technique for lightening bacteria using bacteriophages is unlimited in terms of the bacterial species or the type of bacteria. This method makes it possible to obtain drugs that are remarkable for their ability to modulate the immune system and are prepared from multiple bacteria or a mixture of such bacteria. In particular, these drugs have the ability to induce interferons.
15 Lægemidlet ifølge den foreliggende opfindelse, som modulerer immunresponset, og hvori den aktive bestanddel består af lyse-produkter eller en fraktion af disse produkter fra bakterier, som er lyseret ved hjælp af bakteriofager, er ejendommeligt ved, at det som aktiv bestanddel 20 indeholder det sterile lysefiltrat fra mindst to bakterier, som er lyseret ved hjælp af homologe bakteriofager, idet de udvalgte bakterier er Escherichia coli og Klebsiella pneumoniae.The medicament of the present invention, which modulates the immune response and wherein the active ingredient consists of lysis products or a fraction of these products from bacteria lysed by bacteriophages, is characterized in that it contains as active ingredient 20 it. sterile light filtrate from at least two bacteria lysed by homologous bacteriophages, the bacteria selected being Escherichia coli and Klebsiella pneumoniae.
25 Lægemidlet ifølge opfindelsen kan være kombineret med antibiotika, såsom tetracykliner, et antiviralt middel, såsom syntetiske nucleosider, som griber ind i syntesen af den virale nucleinsyre, et anti-fungusmiddel, som buclosamid, eller et anti-parasitmiddel, som chloroquin.The drug of the invention may be combined with antibiotics such as tetracyclines, an antiviral agent such as synthetic nucleosides which interfere with the synthesis of the viral nucleic acid, an antifungal agent such as buclosamide, or an anti-parasite agent such as chloroquine.
30 Lægemidlet ifølge opfindelsen kan i en anden udførelsesform være kombineret med andre farmaceutiske produkter og præparater, såsom et ant i-tumormiddel (cytostatika), et immunosuppresivt middel (antilymfocytære immunoglobuli-35 ner), et antimitotisk middel, f.eks. folinsyrederivater eller et anti-inflammatorisk middel, f.eks. indomethacin.In another embodiment, the medicament of the invention may be combined with other pharmaceutical products and compositions such as an anti-tumor agent (cytostatic agent), an immunosuppressive agent (antilymphocytic immunoglobulins), an antimitotic agent, e.g. folic acid derivatives or an anti-inflammatory agent, e.g. indomethacin.
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3 Lægemidlet ifølge opfindelsen kan foreligge i forskellige former med henblik på percutan, transcutan, perlingual, topisk, enteral, parenteral eller luftbåren administrering. Afhængig af de enkelte tilfælde tilberedes lægemid-5 let med et passende hjælpestof f.eks. i form af en vandig eller alkoholisk opløsning eller i suspension i et olieholdigt hjælpestof eller i frysetørret form eller som en aerosol eller som en salve.The medicament of the invention may be in various forms for percutaneous, transcutaneous, perlingual, topical, enteral, parenteral or airborne administration. Depending on the individual cases, the drug is prepared with an appropriate adjuvant, e.g. in the form of an aqueous or alcoholic solution or in suspension in an oily auxiliary or in lyophilized form or as an aerosol or as an ointment.
10 Den anvendte dosering er underkastet store variationer afhængig af sammensætningen af lægemidlet, af den beskrevne indikation, af administreringsmåden samt af patientens alder. Bestemmelsen af de anvendte doser foretages af lægen eller dyrlægen, således som det er sædvanlig 15 praksis ved behandlinger for at modulere immunresponset.The dosage used is subject to large variations depending on the composition of the drug, the indication described, the mode of administration and the age of the patient. The doses used are determined by the physician or veterinarian, as is usual practice in treatments to modulate the immune response.
Den daglige dosis kan som eksempel være doser fra 1-50 ml afhængig af koncentrationen af det immunomodulerende præparat ved behandling af kroniske eller recidiverende in-20 fektioner i luftvejene, ved behandling af post-operative infektiøse komplikationer eller ved forebyggelse af urinvej sinfektioner.The daily dose may be, for example, doses ranging from 1-50 ml depending on the concentration of the immunomodulatory preparation in the treatment of chronic or recurrent respiratory tract infections, in the treatment of post-operative infectious complications or in the prevention of urinary tract infections.
Lægemidlet ifølge opfindelsen tolereres særdeles godt, og 25 dets toxicitet er meget lav, således som det vises ved prøven for LD^-q, som man ikke har kunnet måle ved peroral administrering på grund af mavesækskapaciteten hos de anvendte forsøgsdyr (mus og rotter).The drug of the invention is extremely well tolerated and its toxicity is very low, as demonstrated by the sample of LD 2 -q, which could not be measured by oral administration due to the gastric sac capacity of the test animals (mice and rats).
30 Lægemidlet ifølge opfindelsen er i særdeleshed velegnet ved behandlingen af dårligt fungerende immunrespons, ved behandling eller forebyggelse af bakterielle, virale, fungus- eller parasit-infektionsangreb såvel som ved behandlingen af rheumatisme og ved ardannelse eller beskyt-35 telse af sår.The medicament of the invention is particularly suitable in the treatment of malfunctioning immune response, in the treatment or prevention of bacterial, viral, fungal or parasite infections as well as in the treatment of rheumatism and in the scarring or protection of wounds.
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Den foreliggende opfindelsen angår ligeledes en fremgangsmåde til fremstilling af lægemidler af bakterie-ly-se-typen, hvilken fremgangsmåde består af en række på mindst to absolut nødvendige trin, nemlig et bakteriofag-5 lyserende trin og efterfølgende fjernelse af ikke-lyse-rende bakterier og bakterierester ved en for fagmanden kendt fremgangsmåde, som f.eks. filtrering eller centrifugering.The present invention also relates to a process for the preparation of bacterial lysis drugs, which comprises a series of at least two absolutely necessary steps, namely a bacteriophage lysing step and subsequent removal of non-lysis bacteria. and bacterial residues by a method known to those skilled in the art, such as e.g. filtration or centrifugation.
10 Fremgangsmåden ifølge opfindelsen udføres ved at anvende bakterier af forskellig art efter hinanden.The process of the invention is carried out by using bacteria of different kinds one after the other.
Fremgangsmåden er ejendommelig ved, at man poder en første kultur med et inokulum af Klebsiella pneumoniae bak-15 terier, der befinder sig i vækstfasen, at man inficerer Klebsiella-bakterierne ved at indføre deres homologe fager, at man følger udviklingen af lysen indtil et fastlagt stadium, hvorpå man gennemfører en anden podning af kulturen med et inokulum af Escherichia coli bakterier, 20 idet bakterierne af den anden slægt befinder sig i vækstfasen, at man inficerer disse Escherichia bakterier ved at indføre disse bakteriers homologe fager, at man følger lysen af bakterierne af den anden slægt, til et forud fastlagt stadium, hvorefter man fjerner de ikke lyserede 25 bakterier ved kendte metoder ved f.eks. centrifugering eller sterilfiltrering, og at man til sidst opsamler det opnåede lysefiltrat stammende fra de to bakterier.The method is peculiar by grafting a first culture with an inoculum of Klebsiella pneumoniae bacteria that are in the growth phase, infecting the Klebsiella bacteria by introducing their homologous phages, following the evolution of light until a determined stage of conducting another inoculation of the culture with an inoculum of Escherichia coli bacteria, 20 the bacteria of the second genus being in the growth phase, infecting these Escherichia bacteria by introducing the homologous phages of these bacteria, following the light of the bacteria of the second genus, to a predetermined stage, after which the non-lysed bacteria are removed by known methods, e.g. centrifugation or sterile filtration, and eventually collecting the light filtrate obtained from the two bacteria.
Opfindelsen beskrives nærmere i det efterfølgende.The invention is described in more detail below.
30 EKSEMPEL; Fremstilling under successiv anvendelse af bakterier af slægten Klebsiella og Escherichia.EXAMPLE; Production under successive use of bacteria of the genus Klebsiella and Escherichia.
Bakterien af slægten Klebsiella, type pneumoniae, er ka-35 talogiseret af Institut Pasteur i Paris under referencen 58.5.The bacterium of the genus Klebsiella, type pneumoniae, is cataloged by Institut Pasteur in Paris under reference 58.5.
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Bakterien af slægten Escherichia, type coli serotype 0119:B14 er leveret af Institut Pasteur, Paris, som 62.23.The bacterium of the genus Escherichia, type coli serotype 0119: B14 is supplied by Institut Pasteur, Paris, as 62.23.
5 Fagen, en homolog af Klebsiella, tilhører den morfologiske gruppe (nomenklatur under komiteen for taxonomi af bakteriofager under International Committee for Taxonomy of Virus i I.A.M.S.). Den har et ikosaedrisk hoved, en kort hale, som er vanskelig at påvise, kappen og den en-10 destillede plade lader sig ikke konstatere. På agar-agar-substrat har lyse-zonerne en diameter på 0,5-3 mm, og de er af meget uregelmæssig form samt med udviskede konturer og et klart center. Klonerner + er sjældne.5 The phage, a homologue of Klebsiella, belongs to the morphological group (nomenclature of the Committee on Taxonomy of Bacteriophages under the International Committee on Taxonomy of Virus in I.A.M.S.). It has an icosaedric head, a short tail that is difficult to detect, the sheath and the one-distilled plate are not detectable. On agar-agar substrate, the light zones have a diameter of 0.5-3 mm and are of very irregular shape as well as with blurred contours and a clear center. Clone + is rare.
15 Coli-fagen tilhører den morfologiske gruppe (nomenklaturen fra underkomiteen for taxonomi af bakteriofager inden for International Comittee for Taxonomy of Virus under I.A.M.S.). Den har et isometrisk hoved og en meget kort hale, som er vanskelig at påvise, en kappe og en en-20 destillet plade, der ikke lader sig påvise. På gelatinesubstrat har lysé-zonerne en diameter på 1-1,5 mm, rund form, regelmæssige konturer, et tilsløret center og sam- 2Γ + menflydende kloner 25 Dyrkningssubstratet har følgende sammensætning pr. liter: okseekstrakt 3g, pepton 5g, natriumchlorid 7g og resten dobbeltdestilleret vand.15 The coli subject belongs to the morphological group (nomenclature of the subcommittee on taxonomy of bacteriophages within the International Committee on Taxonomy of Virus under I.A.M.S.). It has an isometric head and a very short, hard-to-detect tail, a sheath and a single-distillable, unmistakable plate. On gelatin substrate, the lysine zones have a diameter of 1-1.5 mm, round shape, regular contours, a veiled center, and co-2 + flowing clones. liter: bovine extract 3g, peptone 5g, sodium chloride 7g and the rest double distilled water.
Substratet podes med et inokulum af Klebsiella pneumo-30 niae, som befinder sig i den stationære vækstfase. Den 7 oprindelige tæthed er 1x10 bakterier pr. ml. Kulturen anbringes ved 37 °C under moderat omrøring.The substrate is seeded with an inoculum of Klebsiella pneumoniae which is in the stationary growth phase. The 7 original density is 1x10 bacteria per ml. The culture is placed at 37 ° C with moderate stirring.
Ved afslutningen af nøle-fasen, det vil sige ca. 60 35 minutter efter podningen, inficeres bakterierne med deres homologe fager, idet infektionsstørrelsen er 0,03.At the end of the key phase, that is, approx. 60 minutes after inoculation, the bacteria are infected with their homologous phages, the infection size being 0.03.
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Man følger udviklingen af lysen med en celletæller. Når der er mindre end 10 bakterier pr. ml tilbage, podes substratet påny med et inokulum af Escherichia, der befinder sig i den stationære vækstfase.You follow the evolution of the light with a cell counter. When there are less than 10 bacteria per ml, the substrate is inoculated again with an inoculum of Escherichia, which is in the stationary growth phase.
5 75 7
Den oprindelige tæthed af denne nye kultur er 5x10 Escherichia pr. ml.The original density of this new culture is 5x10 Escherichia per ml.
Ved afslutningen af nøle-fasen, det vil under forsøgs-10 betingelserne sige 20 minutter efter den anden podning, inficeres bakterierne med colifagerne. Infektionsmængden er 0,1.At the end of the nodule phase, that is, under the test conditions, 20 minutes after the second inoculation, the bacteria are infected with the coliphages. The infection rate is 0.1.
Man følger udviklingen af lysen med en celletæller. Når 3 15 der er mindre end 10 Escherichia pr. ml tilbage, afbrydes dyrkningen ved passage gennem et steriliserende membranfilter på 0,22 urn. Det ud fra de to bakterier, Klebsiella pneumoniae og Escherichia coli, opnåede lysefiltrat udgør det immunomodulerende præparat.You follow the evolution of the light with a cell counter. When 3 15 there are less than 10 Escherichia per ml, the culture is interrupted by passage through a 0.22 µm sterilizing membrane filter. The light filtrate obtained from the two bacteria, Klebsiella pneumoniae and Escherichia coli, constitutes the immunomodulatory preparation.
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Virkningen af det omhandlede præparat til mennesker blev afprøvet ved først at blive administreret til en frivillig forsøgsperson og derpå til en syg person.The effect of the present compound in humans was tested by first being administered to a volunteer and then to a sick person.
25 Man gennemførte et dobbelt blindforsøg med 15 frivillige patienter med henblik på at kunne påvise, at den perorale indgift af præparatet efter 10 dages behandling medførte en signifikant forhøjelse af det celleformidlede immunrespons .25 A double blind trial was performed with 15 voluntary patients to demonstrate that the oral administration of the preparation after 10 days of treatment resulted in a significant increase in the cellular mediated immune response.
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En anden undersøgelse, som blev gennemført på 25 patienter, påviste, at en enkelt peroral indgift af forskellige doser af præparatet gjorde det muligt efter 24 timers forløb at inducere en serumlymfokin af typen MIF - LIF.Another study, conducted in 25 patients, showed that a single oral administration of different doses of the preparation allowed the induction of a serum lymphokine of the type MIF - LIF after 24 hours.
35 Denne induction er afhængig af dosens størrelse.This induction is dependent on the size of the dose.
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Adskillige undersøgelser har gjort det muligt at påvise stimuleringen af produktionen af IFN fra humane lymfocytter og monocytter, som var opnået ved cytoferese og dyrket i en såkaldt "speener".Several studies have made it possible to detect the stimulation of IFN production from human lymphocytes and monocytes obtained by cytopheresis and grown in a so-called "weaner".
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Det af præparatet inducerede IFN har kunnet karakteriseres under anvendelse af anti-IFN antisera af typen o, 0 eller r. Produktionen var afhængig af den anvendte dosis.The IFN induced by the composition could be characterized using anti-IFN antisera of type o, 0 or r. Production was dependent on the dose used.
10 I det følgende skal som eksempler anføres nogle kliniske undersøgelser.10 Examples are given below for some clinical studies.
Prævention af og behandling af kroniske eller recidive- rende infektioner i respirationsvejene_ 15Prevention and treatment of chronic or recurrent respiratory tract infections_ 15
Man behandlede to grupper på 25 patienter, som led af kroniske eller recidiverende broncho-pulmonære bakterieinfektioner ved peroral indgift. Den ene gruppe fik 15 ml af det oven for nævnte præparat 20 dage om måneden igen-20 nem 3 måneder, og den anden gruppe modtog klassiske antibiotika-behandlinger. Formindskelsen i antallet af akutte infektions-perioder i de 6 måneder som forsøget varede, var signifikant lavere i den gruppe, som var blevet behandlet med præparatet, end i den gruppe, som var blevet 25 behandlet på klassisk måde med antibiotika.Two groups of 25 patients were treated for chronic or recurrent broncho-pulmonary bacterial infections by oral administration. One group received 15 ml of the above-mentioned preparation 20 days a month again -20 for 3 months, and the other group received classical antibiotic treatments. The decrease in the number of acute infection periods in the 6 months that the trial lasted was significantly lower in the group that had been treated with the preparation than in the group that had been treated in the classic way with antibiotics.
Prævention af post-operative infektionerPrevention of post-operative infections
En peroral indgift på 20 ml af præparatet gjorde det mu-30 ligt signifikant at formindske de post-operative infektions-komplikationer hos 106 patienter i sammenligning med 72 andre syge, som modtog klassisk behandling.An oral administration of 20 ml of the preparation made it possible to significantly reduce the post-operative infection complications in 106 patients compared to 72 other patients who received classical treatment.
Prævention af og behandling af urinvejs-infektioner 35Prevention of and treatment of urinary tract infections 35
Fire forskere har klinisk undersøgt det oven for beskrevne præparat på en gruppe patienter, som led af kroniske 8Four researchers have clinically examined the above-described preparation in a group of patients suffering from chronic 8
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eller recidiverende urinvejsinfektioner.or recurrent urinary tract infections.
En peroral indgift på 15 ml pr. dag 20 dage pr. måned gennem 3 måneder gjorde det muligt signifikant at redu-5 cere hyppigheden og varigheden af infektionsepisoderne, såvel som forbruget af anti-infektionsmidler linder den 6 måneders observationsperiode i sammenligning med de 6 måneder, som gik forud for behandlingen.An oral administration of 15 ml per day. day 20 days per day month through 3 months made it possible to significantly reduce the frequency and duration of the infection episodes, as well as the consumption of anti-infective agents alleviated the 6-month observation period compared to the 6 months preceding treatment.
10 Ved samtlige disse forsøg blev tolerancen over for præparatet bedømt som værende fremragende såvel af lægen som af patienten (frivillig patient såvel som syg patient).In all of these trials, tolerance to the preparation was rated as excellent by both the physician and the patient (voluntary as well as ill patient).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8313362A FR2550707B1 (en) | 1983-08-17 | 1983-08-17 | IMMUNOMODULATOR OF BIOLOGICAL MEDICINE AND PROCESS FOR PREPARING THE SAME |
| FR8313362 | 1983-08-17 |
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| Publication Number | Publication Date |
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| DK393884D0 DK393884D0 (en) | 1984-08-16 |
| DK393884A DK393884A (en) | 1985-02-18 |
| DK160807B true DK160807B (en) | 1991-04-22 |
| DK160807C DK160807C (en) | 1991-10-07 |
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| JP (1) | JPS6069022A (en) |
| AT (1) | ATE36240T1 (en) |
| AU (1) | AU564652B2 (en) |
| CA (1) | CA1229566A (en) |
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| DE (1) | DE3473228D1 (en) |
| DK (1) | DK160807C (en) |
| ES (1) | ES8602415A1 (en) |
| FR (1) | FR2550707B1 (en) |
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| US4876194A (en) * | 1986-07-22 | 1989-10-24 | Hightech Receptor Ab | Protein L and subfragments thereof, with immunoglobulin binding activity, a process for preparing thereof, reagent kit, pharmaceutical composition and a peptococcus magnus strain |
| FR2620130B1 (en) * | 1987-09-08 | 1990-01-12 | Lipha | NOVEL WATER-SOLUBLE POLYSACCHARIDES, PROCESS FOR OBTAINING THEM, USE THEREOF AS MEDICAMENTS AND PREPARATION CONTAINING THEM |
| IL88480A0 (en) * | 1987-11-27 | 1989-06-30 | Univ Toronto | Proteinaceous compositions |
| WO1997045530A1 (en) * | 1996-05-27 | 1997-12-04 | UZILOVA, Irina Semenovna, Heiress of UZILOV | Use of streptococcus faecium strains and composition containing the same |
| ATE421249T1 (en) * | 2002-02-13 | 2009-02-15 | Immunology Lab Inc | COMPOSITIONS AND METHODS FOR THE TREATMENT OF MICROORGANISM INFECTIONS |
Family Cites Families (4)
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|---|---|---|---|---|
| BE758977A (en) * | 1969-11-17 | 1971-05-17 | Glaxo Lab Ltd | BIOCHEMICAL PROCESS |
| CH633188A5 (en) * | 1978-05-26 | 1982-11-30 | Om Laboratoires Sa | MEDICINE FOR INFECTIOUS DISEASES OF THE RESPIRATORY TRACT. |
| CH639852A5 (en) * | 1979-07-26 | 1983-12-15 | Om Laboratoires Sa | MEDICINE AGAINST INFECTIOUS DISEASES OF THE URINARY AND DIGESTIVE PATHWAYS. |
| US4322405A (en) * | 1981-04-06 | 1982-03-30 | Laboratoires Om Societe Anonyme | Method for treating rheumatoid arthritis |
-
1983
- 1983-08-17 FR FR8313362A patent/FR2550707B1/en not_active Expired
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1984
- 1984-07-31 CA CA000460042A patent/CA1229566A/en not_active Expired
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- 1984-08-06 IN IN629/DEL/84A patent/IN161616B/en unknown
- 1984-08-06 IL IL72589A patent/IL72589A/en unknown
- 1984-08-08 ZA ZA846151A patent/ZA846151B/en unknown
- 1984-08-08 DE DE8484401647T patent/DE3473228D1/en not_active Expired
- 1984-08-08 EP EP84401647A patent/EP0139551B1/en not_active Expired
- 1984-08-08 AT AT84401647T patent/ATE36240T1/en not_active IP Right Cessation
- 1984-08-10 NZ NZ209171A patent/NZ209171A/en unknown
- 1984-08-15 AU AU31938/84A patent/AU564652B2/en not_active Ceased
- 1984-08-16 HU HU843107A patent/HU193217B/en not_active IP Right Cessation
- 1984-08-16 NO NO843274A patent/NO843274L/en unknown
- 1984-08-16 PT PT79090A patent/PT79090B/en not_active IP Right Cessation
- 1984-08-16 DK DK393884A patent/DK160807C/en not_active IP Right Cessation
- 1984-08-16 ES ES535213A patent/ES8602415A1/en not_active Expired
- 1984-08-16 MA MA20427A patent/MA20203A1/en unknown
- 1984-08-16 SU SU843781693A patent/SU1487815A3/en active
- 1984-08-17 DD DD84266389A patent/DD232432A5/en not_active IP Right Cessation
- 1984-08-17 YU YU01432/84A patent/YU143284A/en unknown
- 1984-08-17 JP JP59170515A patent/JPS6069022A/en active Pending
- 1984-08-17 OA OA58368A patent/OA07794A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0139551A2 (en) | 1985-05-02 |
| FR2550707A1 (en) | 1985-02-22 |
| IL72589A (en) | 1988-01-31 |
| DD232432A5 (en) | 1986-01-29 |
| JPS6069022A (en) | 1985-04-19 |
| ES535213A0 (en) | 1985-12-01 |
| DK393884D0 (en) | 1984-08-16 |
| ES8602415A1 (en) | 1985-12-01 |
| IN161616B (en) | 1988-01-02 |
| ATE36240T1 (en) | 1988-08-15 |
| FR2550707B1 (en) | 1986-02-28 |
| NO843274L (en) | 1985-02-18 |
| HUT35013A (en) | 1985-05-28 |
| AU3193884A (en) | 1985-02-21 |
| DE3473228D1 (en) | 1988-09-15 |
| CA1229566A (en) | 1987-11-24 |
| ZA846151B (en) | 1985-03-27 |
| CS592184A2 (en) | 1989-11-14 |
| OA07794A (en) | 1986-11-20 |
| PT79090A (en) | 1984-09-01 |
| SU1487815A3 (en) | 1989-06-15 |
| EP0139551B1 (en) | 1988-08-10 |
| HU193217B (en) | 1987-08-28 |
| DK160807C (en) | 1991-10-07 |
| YU143284A (en) | 1991-02-28 |
| IL72589A0 (en) | 1984-11-30 |
| PT79090B (en) | 1986-08-14 |
| DK393884A (en) | 1985-02-18 |
| AU564652B2 (en) | 1987-08-20 |
| CS270410B2 (en) | 1990-06-13 |
| NZ209171A (en) | 1988-10-28 |
| MA20203A1 (en) | 1985-04-01 |
| EP0139551A3 (en) | 1985-07-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |