NL8503413A - PREPARATIONS FOR THE PREVENTION OF DIARRHEE. - Google Patents
PREPARATIONS FOR THE PREVENTION OF DIARRHEE. Download PDFInfo
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- NL8503413A NL8503413A NL8503413A NL8503413A NL8503413A NL 8503413 A NL8503413 A NL 8503413A NL 8503413 A NL8503413 A NL 8503413A NL 8503413 A NL8503413 A NL 8503413A NL 8503413 A NL8503413 A NL 8503413A
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- phenylalanine
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- adhesin
- isoleucine
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- 230000002265 prevention Effects 0.000 title description 2
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 claims description 14
- 206010012735 Diarrhoea Diseases 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 8
- 210000004347 intestinal mucosa Anatomy 0.000 claims description 7
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 7
- 150000001413 amino acids Chemical group 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 230000000903 blocking effect Effects 0.000 claims description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- 229960000310 isoleucine Drugs 0.000 claims 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 1
- 239000000427 antigen Substances 0.000 description 10
- 102000036639 antigens Human genes 0.000 description 10
- 108091007433 antigens Proteins 0.000 description 10
- 241000588724 Escherichia coli Species 0.000 description 8
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- 108020003175 receptors Proteins 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 231100000249 enterotoxic Toxicity 0.000 description 5
- 230000002242 enterotoxic effect Effects 0.000 description 5
- 238000002255 vaccination Methods 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 3
- 244000309466 calf Species 0.000 description 3
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- 102000035195 Peptidases Human genes 0.000 description 2
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- 230000029087 digestion Effects 0.000 description 2
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000035931 haemagglutination Effects 0.000 description 1
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- 230000006698 induction Effects 0.000 description 1
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- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K14/245—Escherichia (G)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Description
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Preparaten ter bestrijding van diarrhee.Preparations to combat diarrhea.
De belangrijkste verwekkers van neonatale diarrhee bij zowel mens als dier zijn de enterotoxische E. coli stammen. Bij zuigelingen of zeer jonge kinderen en bij pasgeboren vee heeft deze infectie vrijwel zonder uitzondering een lethaal verloop; 5 Uit recente cijfers van de WHO blijkt dat jaarlijks 500 miljoen baby's en jonge kinderen (voornamelijk in de ontwikkelingslanden) last hebben van diarrhee met meer dan 5 miljoen slachtoffers.The major pathogens of neonatal diarrhea in both humans and animals are the enterotoxic E. coli strains. In infants or very young children and in newborn cattle, this infection almost without exception has a lethal course; 5 Recent WHO figures show that 500 million babies and young children (mainly in developing countries) suffer from diarrhea with more than 5 million victims annually.
Naast V. cholerae blijkt E. coli de belangrijkste verwekker. Bij slachtvee zijn geen betrouwbare cijfers bekend maar het verlies 10 loopt zeker in de miljarden per jaar.In addition to V. cholerae, E. coli appears to be the most important causative agent. No reliable figures are known for beef cattle, but the loss 10 certainly runs into billions per year.
Enterotoxische E. coli stammen onderscheiden zich van commensale niet-pathogene stammen door het bezit van een tweetal belangrijke virulentie factoren te weten: de produktie van enterotoxinen en de aanwezigheid van adhesie-antigenen. De adhesie-15 antigenen van E. coli bestaan uit elektronen-microscopisch zichtbare draadachtige aanhangsels op het bacterie oppervlak aangeduid als fimbriae of pili. Deze fimbriae blijken te zijn opgebouwd uit honderden identieke eiwit sübeenheden met een moleculairgewicht in de orde van grootte van 25.000. Middels de 20 fimbriae blijkt de bacterie in staat het darmepitheel te koloniseren en op deze wijze de darm.te prolifereren. Zodra de kolonisatie tot stand is gekomen zorgt het geproduceerde en uitgescheiden entero-toxine voor het ontstaan van de diarrhee.Enterotoxic E. coli strains differ from commensal non-pathogenic strains by possessing two important virulence factors, namely the production of enterotoxins and the presence of adhesion antigens. The E. coli adhesion antigens consist of electron microscopically visible thread-like appendages on the bacterial surface referred to as fimbriae or pili. These fimbriae appear to be made up of hundreds of identical protein fragments with a molecular weight of the order of 25,000. By means of the fimbriae, the bacterium appears to be able to colonize the intestinal epithelium and in this way proliferate the intestine. Once colonization is established, the produced and secreted entero-toxin causes the diarrhea to form.
Experimenten met gemuteerde stammen die hetzij geen adhesie-25 antigenen, hetzij geen enterotoxine meer kunnen produceren hebben uitgewezen dat deze stammen of geen of een zeer lichte, voorbijgaande, vorm van diarrhee opwekken.Experiments with mutated strains that are either unable to produce adhesion antigens or enterotoxin have shown that these strains induce either none or a very mild transient form of diarrhea.
Reeds geruimte tijd houden diverse onderzoeksgroepen zich bezig met de vraag of preventie van dit type infecties middels 30 inductie van beschermende antilichamen mogelijk is. Gebleken is dat toediening van toxoid weliswaar antitoxine immuunglobulinen opwekt C54 Π -i '*·% - 2 - maar dat deze antilichamen geen of slechts gedeeltelijke bescherming geven.For quite some time, various research groups have been examining whether prevention of this type of infection is possible by induction of protective antibodies. It has been found that although administration of toxoid induces anti-toxin immune globulins C54 Π -i '*% - 2 - these antibodies provide no or only partial protection.
Een tweede benadering berust op het induceren van antilichamen gericht tegen de adhesie-an tig en en·. Deze benadering is succesvol 5 gebleken. Vaccinatie met gezuiverde adhesine preparaten blijkt in de meeste gevallen een voldoend hoge respons van beschermende antilichamen op te leveren om pasgeboren nakomelingen tegen de infectie te beschermen. Al deze experimenten betreffen infecties bij biggen, kalveren of lammeren. Meerdere firma's brengen dit 10 type vaccins op de markt.A second approach relies on inducing antibodies directed against the adhesion inhibitors and and. This approach has proven successful 5. Vaccination with purified adhesin preparations has been found in most cases to produce a sufficiently high response of protective antibodies to protect newborn offspring from infection. All these experiments concern infections in piglets, calves or lambs. Several companies market these 10 types of vaccines.
Een probleem bij de vaccinatie van slachtvee met gezuiverde antigeenpreparaten is de omstandigheid dat E. coli meerdere verschillende adhesie-antigenen kan produceren zodat nu reeds duidelijk is dat aan commerciële vaccins steeds meer verschillende 15 adhesie-antigenen moeten worden toegevoegd.A problem in the vaccination of slaughtered cattle with purified antigen preparations is the fact that E. coli can produce several different adhesion antigens, so that it is already clear that more and more different adhesion antigens must be added to commercial vaccines.
Sommige stammen produceren slechts één, andere kunnen 2 of zelfs 3 adhesie-antigenen tegelijkertijd synthetiseren.Some strains produce only one, others can synthesize 2 or even 3 adhesion antigens at the same time.
Een tweede probleem samenhangend met dit type bestrijding is dat vaccinatie van de ouder-dieren (runderen, zeugen) weliswaar 20 preventief werkt en de nakomelingen beschermt, maar gezien de daaraan verbonden kosten doorgaans slechts wordt toegepast op probleembedrijven. Therapeutisch heeft vaccinatie op het moment dat de infectie zich openbaart uiteraard geen enkele zin.A second problem associated with this type of control is that, although vaccination of the parent animals (cattle, sows) has a preventive effect and protects the offspring, given the associated costs, it is usually only applied to problem farms. Therapeutically, vaccination is of no use at the time the infection manifests itself.
Gezien het feit dat vaccinatie doorgaans slechts wordt 25 toegepast in geval problemen te verwachten zijn wordt op grote schaal diarrhee nog steeds bestreden met antibiotica, met alle nadelen van dien (kosten, neveneffecten, etc.). Gezocht wordt daarom naar andere vormen van therapie.- De benadering die daarbij wordt gekozen is gericht op het voorkómen van kolonisatie d.w.z.Given that vaccination is usually only applied when problems are expected, diarrhea is still widely combated with antibiotics, with all the associated drawbacks (costs, side effects, etc.). Therefore, we are looking for other forms of therapy.- The approach that is taken is aimed at preventing colonization, i.e.
30 van aanhechting van de bacteriën aan het darmpitheel. Het is mogelijk gebleken diarrhee te bestrijden door orale toediening van (monoclonale) antilichamen gericht tegen de adhesie-antigenen op het bacterie-oppervlak. Een eerste preparaat ter bestrijding 3 o C 3 4 1 3 ψ· _ - 3 - van neonatale diarrhee bij kalveren is thans commercieel verkrijgbaar (Molecular Genetics) maar er is nog betrekkelijk weinig over het succes bekend. Nadelen zijn onder andere de kosten en de houdbaarheid van het preparaat.30 of attachment of the bacteria to the intestinal epithelium. It has been found possible to combat diarrhea by oral administration of (monoclonal) antibodies directed against the adhesion antigens on the bacterial surface. A first preparation to control neonatal diarrhea in calves 3 o C 3 4 1 3 3 · _ - 3 is currently commercially available (Molecular Genetics), but relatively little is known about its success. Disadvantages include the cost and shelf life of the preparation.
5 Bovengenoemde therapeutische benadering is gericht tegen het infecterend micro-organisme. Gebleken is nu, dat een nieuwe therapie kan worden gericht op het blokkeren van de adhesine-receptoren aanwezig op het darmepitheel.The above therapeutic approach is directed against the infecting microorganism. It has now been found that a new therapy can be aimed at blocking the adhesin receptors present on the intestinal epithelium.
Tot voor kort was nog van geen enkel adhesine van entero-10 toxische Ξ. coli-stammen bekend welk structuuronderdeel (of onderdelen) van belang zijn voor de receptorherkenning.Until recently, no enterin-10 adhesin was toxic Ξ. coli strains known which structural part (s) are important for receptor recognition.
Verrassenderwijs is nu gebleken, dat het hier ruimtelijk zeer beperkte structuren betreft.Surprisingly, it has now been found that these are very limited spatial structures.
Eén van de adhesie-antigenen bij enterotoxische E. coli-stam-15 men uit biggen wordt aangeduid als K88. Van het K88 adhesine zijn drie varianten bekend die immunologisch goed te onderscheiden zijn.One of the adhesion antigens in piglet enterotoxic E. coli strains is designated K88. Three variants of the K88 adhesin are known, which are clearly distinguishable immunologically.
Van elk van deze varianten is de primaire structuur van de subeenheid waaruit het adhesine is opgebouwd door ons volledig opgehelderd. Naast geconserveerde gebieden (identieke aminozuur-20 sequenties in de subeenheidvarianten) blijken op bepaalde plaatsen variabele aminozuursequenties voor te komen waarmee de drie varianten zich van elkaar onderscheiden. Bij digesties van gedenatureerde subeenheden met proteolytische enzymen is nu gebleken, dat van elke variant fragmenten geïsoleerd kunnen worden die de 25 binding van de adhesine-dragende bacteriën aan erythrocyten (haemagglutinatie reactie) of aan darmepitheelcellen reeds in lage concentraties kunnen blokkeren. Deze fragmenten zijn afkomstig uit de geconserveerde delen van de subeenheid varianten. Analyse van drie geïsoleerde fragmenten heeft uitgewezen, dat het hier om de 30 volgende tripeptiden gaat: serine-leucine-phenylalanine, isoleucine-alanine-phenylalanine en alanine-isoleucine-phenylalanine. Deze peptiden zijn bestand tegen afbraak door proteolytische enzymen uit het maag-darmkanaal.Of each of these variants, the primary structure of the subunit that makes up the adhesin has been fully elucidated by us. In addition to conserved regions (identical amino acid-20 sequences in the subunit variants), variable amino acid sequences with which the three variants are distinguished appear to occur in certain places. Digestions of denatured subunits with proteolytic enzymes have now shown that fragments can be isolated from each variant which can already block the binding of the adhesin-bearing bacteria to erythrocytes (haemagglutination reaction) or to intestinal epithelial cells in low concentrations. These fragments are from the conserved parts of the subunit variants. Analysis of three isolated fragments has shown that these are the following three tripeptides: serine-leucine-phenylalanine, isoleucine-alanine-phenylalanine and alanine-isoleucine-phenylalanine. These peptides are resistant to digestion by proteolytic enzymes from the gastrointestinal tract.
6303413 -i - - 4 -6303413 -i - - 4 -
Alle drie de geïsoleerde en geïdentificeerde tripeptiden zijn synthetisch nagemaakt. De synthetische peptiden bezitten dezelfde werkzaamheid en activiteit als de uit het adhesine geïsoleerde peptiden.All three isolated and identified tripeptides are synthetically counterfeited. The synthetic peptides have the same activity and activity as the peptides isolated from the adhesin.
5 In het K88 adhesine komen derhalve op bepaalde plaatsen bekende aminozuursequenties voor die sterke affiniteit vertonen voor de adhesine-receptoren. Deze aminozuursequenties vormen daarom mogelijkerwijs een essentieel onderdeel van de natuurlijke receptorbindingsplaats.Thus, in the K88 adhesin known amino acids sequences occur at certain locations which show strong affinity for the adhesin receptors. These amino acid sequences may therefore form an essential part of the natural receptor binding site.
10 Voorlopig onderzoek aan het adhesine-antigeen K99 van enterotoxische E. coli-stammen uit kalveren en lammeren wijst erop, dat ook hier ruimtelijk zeer beperkte structuren verantwoordelijk zijn voor aanhechting aan de receptor.Preliminary research on the adhesin antigen K99 of enterotoxic E. coli strains from calves and lambs indicates that here too very spatially limited structures are responsible for attachment to the receptor.
Aangezien bovengenoemde peptiden als het ware een 15 imitatie vormen van de natuurlijke receptorbindingsplaats zoals die voorkomt op het adhesine aan het bacterie-oppervlak, zullen deze peptiden in de darm met de bacterie competeren voor aanhechting aan het darmepitheel. Ook eenmaal gebonden bacteriën zullen door de peptiden van het darmepitheel verwijderd kunnen worden.Since the above peptides imitate, as it were, the natural receptor binding site as it occurs on the adhesin to the bacterial surface, these peptides in the intestine will compete with the bacterium for adhesion to the intestinal epithelium. Once bound, bacteria will also be able to be removed from the intestinal epithelium by the peptides.
20 Gezien de korte duur van de infectie (1-2 dagen) zal blokkade van de darmepitheelreceptoren slechts van korte duur behoeven te zijn. Deze inperking van de blokkade in de tijd wordt door de gastheer zelf bewerkstelligd aangezien darmepitheel-cellen (enterocyten) in snel tempo (doorgaans binnen 24 uur) door 25 nieuwe aanmaak worden vervangen en losgelaten.In view of the short duration of the infection (1-2 days), blockage of the intestinal epithelial receptors should only be of short duration. This containment of the blockage over time is accomplished by the host itself as intestinal epithelial cells (enterocytes) are rapidly replaced (released within 24 hours) and released.
Op grond van bovenstaande uitvinding zal men in voedsel of in therapeutische preparaten stoffen met de bedoelde ruimtelijk zeer beperkte structuren opnemen.On the basis of the above invention, substances with the intended spatially very limited structures will be incorporated in food or in therapeutic preparations.
De mogelijk optredende opname van deze stoffen door het 30 darmepitheel kan voorkómen worden door de stoffen aan inerte macromoleculaire dragers te koppelen.The possible uptake of these substances by the intestinal epithelium can be prevented by coupling the substances to inert macromolecular carriers.
De bovengenoemde ruimtelijk zeer beperkte structuren zoals tripeptiden zijn goedkoop te isoleren of te synthetiseren en goed 8303413 - 5 - *** houdbaar. Zij hebben, geen nadelige effecten op de gastheer.The above spatially very limited structures such as tripeptides are inexpensive to isolate or synthesize and have a good shelf life. They have no adverse effects on the host.
Naast toepassing bij pasgeboren nakomelingen kunnen de therapeutische preparaten volgens de uitvinding ook bij volwassenen gebruikt worden ter bestrijding van diarrhee veroor-5 zaakt door enterotoxische E. coli-stammen.In addition to use in newborn offspring, the therapeutic compositions of the invention can also be used in adults to control diarrhea caused by enterotoxic E. coli strains.
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Claims (7)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8503413A NL8503413A (en) | 1985-12-11 | 1985-12-11 | PREPARATIONS FOR THE PREVENTION OF DIARRHEE. |
| EP19860906963 EP0248838A1 (en) | 1985-12-11 | 1986-12-09 | Compositions for combatting diarrhoea |
| JP62500023A JPS63501950A (en) | 1985-12-11 | 1986-12-09 | Composition for treating diarrhea |
| PCT/NL1986/000041 WO1987003485A1 (en) | 1985-12-11 | 1986-12-09 | Compositions for combatting diarrhoea |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8503413A NL8503413A (en) | 1985-12-11 | 1985-12-11 | PREPARATIONS FOR THE PREVENTION OF DIARRHEE. |
| NL8503413 | 1985-12-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8503413A true NL8503413A (en) | 1987-07-01 |
Family
ID=19847002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8503413A NL8503413A (en) | 1985-12-11 | 1985-12-11 | PREPARATIONS FOR THE PREVENTION OF DIARRHEE. |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0248838A1 (en) |
| JP (1) | JPS63501950A (en) |
| NL (1) | NL8503413A (en) |
| WO (1) | WO1987003485A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK53291D0 (en) * | 1991-03-25 | 1991-03-25 | Carlbiotech Ltd As | SMALL PEPTIDES AND PEPTID RELATED SUBSTANCES AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH COMPOUNDS |
| US6818585B2 (en) * | 1998-12-30 | 2004-11-16 | Univation Technologies, Llc | Catalyst compounds, catalyst systems thereof and their use in a polymerization process |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU76538A1 (en) * | 1977-01-07 | 1978-09-18 | ||
| SU921712A1 (en) * | 1979-12-10 | 1982-04-23 | Ереванский политехнический институт им.К.Маркса | Machine tool for working crank shaft connecting rod necks |
| DE3213740A1 (en) * | 1982-04-14 | 1983-12-15 | Oerlikon-Boehringer GmbH, 7320 Göppingen | Whirl device |
| JPS591101A (en) * | 1982-05-24 | 1984-01-06 | Komatsu Ltd | crankshaft mirror |
-
1985
- 1985-12-11 NL NL8503413A patent/NL8503413A/en not_active Application Discontinuation
-
1986
- 1986-12-09 EP EP19860906963 patent/EP0248838A1/en not_active Withdrawn
- 1986-12-09 JP JP62500023A patent/JPS63501950A/en active Pending
- 1986-12-09 WO PCT/NL1986/000041 patent/WO1987003485A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63501950A (en) | 1988-08-04 |
| WO1987003485A1 (en) | 1987-06-18 |
| EP0248838A1 (en) | 1987-12-16 |
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