[go: up one dir, main page]

WO1992010204A1 - Lectines probiotiques - Google Patents

Lectines probiotiques Download PDF

Info

Publication number
WO1992010204A1
WO1992010204A1 PCT/GB1991/002236 GB9102236W WO9210204A1 WO 1992010204 A1 WO1992010204 A1 WO 1992010204A1 GB 9102236 W GB9102236 W GB 9102236W WO 9210204 A1 WO9210204 A1 WO 9210204A1
Authority
WO
WIPO (PCT)
Prior art keywords
lectin
tissue
lectins
toxic
substantially non
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1991/002236
Other languages
English (en)
Inventor
Arpad Janos Pusztai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rowett Research Institute
Original Assignee
Rowett Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rowett Research Institute filed Critical Rowett Research Institute
Priority to JP4502133A priority Critical patent/JPH06504533A/ja
Publication of WO1992010204A1 publication Critical patent/WO1992010204A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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

Definitions

  • This invention relates to probiosis, and especially to the use of lectins in blocking attachment sites on tissue to prevent the attachment of undesirable entities on these sites.
  • the binding of the entities is sugar-specific as a result of the activity of lectins (also known as adhesins and lectin-adhesins, particularly in the context of bacteria, and agglutinins) which are carried by the entities.
  • lectins also known as adhesins and lectin-adhesins, particularly in the context of bacteria, and agglutinins
  • Lectins are proteins or glycoproteins of a non- immunoglobulin nature which recognise specific sugar residues and bind to them, generally in a reversible manner without causing any covalent modification to the structure of the carbohydrate ligand.
  • the lectin-carrying microorganism or parasite can multiply and thereby poison or cause damage to the animal.
  • the binding of lectins to sugar residues is known, but in general the studies that have been undertaken have considered only the nature of the binding and not any practical benefits and uses that may derive therefrom.
  • a substantially non-toxic lectin or lectin-carrying entity in the manufacture of a medicament for the treatment or prevention of a disease or condition caused by undesirable entities capable of lectin-mediated binding to tissue.
  • Substantially non-toxic lectins are innocuous or beneficial to animal tissue, when compared with the toxic, harmful or other undesirable lectin or lectin- carrying entity whose attachment to tissue is sought to be prevented. This should not be taken to suggest that the only lectins which can be used in the invention are those which are free of side effects (although they are of course preferred) ; rather, any lectin or lectin- carrying entity can be used provided that, overall, the consequences of attachment to tissue are preferable to those resulting from the attachment of the microorganism or parasite.
  • Lectins suitable for use in this invention are generally of plant origin. They include those obtainable from
  • Amaryllidacea Lilaceae , Iridaceae and Alliaceae.
  • Preferred members of the families Amaryllidaceae include
  • Preferred members of the family Iridaceae include irises while those of the family Liliaceae (or Alliaceae) include Allium spp. such as garlic.
  • the precise lectin preferred for any particular application of the invention will depend on the microorganism or parasite whose attachment to tissue is unwanted.
  • the therapeutic (or prophylactic) lectin may compete with bacterial or other microorganism or parasite lectin for attachment to surface receptors on tissue, or it may cause the expression of surface receptors to change.
  • the therapeutic lectin should be matched to the undesirable lectin, for example by reference to the sugars to which both of them can bind.
  • an undesirable entity targets mannose or lactose
  • a mannose-specific or lactose- specific lectin can be used.
  • Specificity of lectins can readily be matched by agglutination studies, which therefore provide a means for determining suitable lectins for use in the invention.
  • the mannose-specific Galanthus nivalis agglutinin has been shown to bind to sites in the small intestine and is therefore a useful lectin for inclusion in the invention with the specific aim to be used for the prevention of mannose-specific lectin-carrying microorganisms, parasites or other harmful entities. In this way, mannose-specific E. coli poisoning can be prevented or controlled.
  • GNA can be isolated from snowdrop bulbs by the method of Van Damme et al . (FEBS Letters 215 140-144 (1987)).
  • the invention is not, at its broadest, limited to any particular sugar or combination of them. Even though lectins are proteins or glycoproteins, some of them (including GNA) seem to survive passage through the gut almost quantitatively (Van Damme et al . , loc. cit. ) .
  • the survival rate might be at least 20% or more.
  • This fact has implications for the formulation or presentation of lectins in the use of the invention.
  • the lectin may of course be administered orally, as will be discussed below.
  • the provision of a suitable carrier or means of protection is not ruled out and may be desirable under certain circumstances, such as when the less gut-stable lectins are to be used.
  • the therapeutic lectin may therefore be administered as a "lectin-carrying entity", which overall should have appropriate toxicity characteristics for the particular circumstances of use.
  • lectins of various specificities can be isolated from plants.
  • the invention is not restricted to those lectins which have naturally been synthesised in a growing plant.
  • tissue culture may be used to produce suitable lectins.
  • recombinant DNA technology means that lectins can be produced in heterologous host cells and also enables the structure of lectins to be varied to suit particular circumstances.
  • the use of synthetic lectins, whether or not corresponding to natural lectin, is not ruled out.
  • Many natural lectins are available commercially, for example from Sigma Chemical Co. Ltd. , Poole, Dorset, United Kingdom.
  • the invention is useful in combatting the effects of lectin-carrying microorganisms, parasites and, generally, other undesirable organisms and entities. Frequently, the invention will be used to counter or prevent the effects of lectin-carrying bacteria.
  • Bacteria against which the invention may be used with considerable effect are varied. They include Escherichia spp. (such as Escherichia coli) , Salmonella spp. (such as Salmonella enteriditis , S. typhi and S. typhimiurium) , Lactobacillus spp. and non-lactose-fermenting coliforms including Proteus spp. (such as Proteus mirabilis) , to give only a few examples.
  • Escherichia spp. such as Escherichia coli
  • Salmonella spp. such as Salmonella enteriditis , S. typhi and S. typhimiurium
  • Lactobacillus spp. and non-lactose-fermenting coliforms including Proteus spp. (such as Proteus mirabilis)
  • Proteus spp. such as Proteus mirabilis
  • the invention may give protection not only against microorganisms usually regarded as pathogens but also against harmful effects of those not normally so regarded.
  • high bacterial numbers of commensal and/or opportunistic bacteria such as non-toxic E. coli
  • severe diarrhoea a symptom of the so-called "non-specific colitis”
  • Some substances are toxic because they cause bacterial overgrowth, and the harmful consequences just mentioned; included within this group of substances are, paradoxically, certain plant lectins such as Phaseolus vulgaris agglutinin (PHA) , which will be discussed below.
  • PHA Phaseolus vulgaris agglutinin
  • Fi bria Bacterial "lectins" (more often called adhesins in this context) are usually carried by fi bria. Such fimbrial adhesins can have specificity for a variety of sugars (including but by no means limited to glucose, galactose, lactose, N-acetylamino-sugars such as N- acetylglucosamine, N-acetylgalactosamine and others, such as ⁇ -2,6-neuraminylgalactose) , but in the case of at least some strains of E. coli and certain Salmonella spp. they are mannose-specific.
  • sugars including but by no means limited to glucose, galactose, lactose, N-acetylamino-sugars such as N- acetylglucosamine, N-acetylgalactosamine and others, such as ⁇ -2,6-neuraminylgalactose
  • E. coli bind to the cells of the small intestine wall through mannose or other sugar residues on the wall which are targeted by lectin carried by the bacterium. These mannose sugar residues occur mainly in the crypt cells which are not accessible to bacteria. However, with the addition of other sugar residues during the normal course of differentiation and maturation of crypt cells, as the cells move up the intestinal villi, the original mannose groups become gradually submerged in more complex structures. These then no longer serve as attachment points for the mannose-specific lectin-adhesin of E. coli . Thus under normal conditions relatively few E. coli cells will be bound to the villus tip cells.
  • PHA Phaseolu ⁇ vulgaris agglutinin
  • this effect and the toxic effects of similarly acting agents, can be prevented or treated as the substantially non-toxic (that is to say innocuous or beneficial) lectins occupy sites on the villi thereby denying these sites to the bacteria which then travel on through and out of the intestine.
  • tissues to which lectin-carrying entities bind include the gastrointestinal tract in general and the gut in particular. From the point of view of nutrition and health, the small intestine is the most important part of the gut, but this consideration does not mean that other tissues which may be either part of or separate from the gastrointestinal tract cannot be treated by the invention. Tissues forming part of the gut to which the invention may be applied include the caecum and the large intestine; other tissues include the urethra, the trachea and other (wounded or healthy) tissue open to invasion and infection from the outside world.
  • the invention finds application in both human and veterinary medicine, as well as in animal husbandry.
  • the present invention may be employed in the treatment or prophylaxis of disease or other medical or veterinary conditions.
  • the lectin of the blocking agent is preferably administered in quantities sufficient to compete effectively with, and preferably to exceed, the quantities of the undesirable entities already bound or attached to the tissue.
  • the lectin of the blocking agent binds to sugar residues on tissue to prevent or reduce attachment of harmful lectin-carrying entities. Doses for treatment of an existing condition will therefore be likely to be lower than prophylactic doses (which would include doses routinely or occasionally added to feeds) .
  • doses include those in the range of from 0.001 to 0.5 g/kg body weight (per dose or per day), possibly about 0.05 g/kg body weight.
  • the lectin in this invention is administered over a period of days instead of in a single dose.
  • a single dose of lOmg of GNA was administered to rats and the small intestine examined after one hour, no binding of GNA to the intestine wall was observed.
  • other lectins of the same family for example from daffodil bulbs, iris bulbs and garlic cloves.
  • a dose of 42mg administered each day for 10 days resulted in strong binding being observed.
  • Lectins are preferred for oral administration. Their ability to withstand the conditions of the stomach and other regions of the gastrointestinal tract make them particularly appropriate for administration by this route. However, other routes of administration are also contemplated. Rectal administration and, at least in some indications, parenteral administration may sometimes be appropriate. Formulations for parenteral administration will generally be sterile.
  • Treatment in accordance with the invention may be accompanied by fasting or a lesser dietary restriction. Under such circumstances the substantially non-toxic lectins are observed to be more effective. The reasons for this are varied, but are consistent with the common human experience of loss of appetite coupled to gastrointestinal infection.
  • a substantially non-toxic lectin or lectin- carrying entity for use in medicine, particularly in the prevention or treatment of infection or infestation by infectious or infesting agents whose attachment to tissue is lectin-mediated.
  • a pharmaceutical or veterinary composition comprising a lectin or lectin-carrying entity and a pharmaceutically or veterinarily acceptable carrier.
  • compositions may be in solid or liquid form and will contain suitable excipients, according to the intended mode of administration
  • a method of rearing an animal comprising administering to the animal a suitable diet supplemented with one or more substantially non-toxic lectins capable of preventing or reducing the attachment of lectins carried by an undesirable microorganism or parasite.
  • an animal foodstuff comprising one or more substantially non-toxic lectins capable of preventing or reducing the attachment . of lectins carried by an undesirable microorganism or parasite.
  • the invention involves, in general, a method of blocking attachment sites on tissue, the attachment sites on tissue comprising one or more sugar residues, the method comprising contacting the tissue with a lectin or lectin-carrying entity which is innocuous or beneficial to the body containing said tissue.
  • the overgrowth of non-pathogenic, mannose-fimbriated E . coli is induced by increasing the number of mannose-receptors in the small intestinal brush border by dietary exposure to the lectin PHA, from the seeds of kidney bean (Phaseolus vulgaris) .
  • This lectin induces extensive hyperplastic growth of the small intestine and, by speeding up the migration of cells from the crypts into the absorptive villi, reduces the time available for cells to differentiate and mature.
  • With the consequent increase in the number of mannose- receptors of epithelial cells more points of attachment for E. coli are generated leading to their overgrowth in the small intestine. With the input of 30-40mg of PHA/rat/day levels of E.
  • GNA mannose-specific lectin
  • mice Male Hooded-Lister rats of the Rowett colony were used. Their average weight was 80-85g and their pre-experimental diet was the control diet (6 g/rat/day) .
  • the lactalbumin protein-based control diet (lOOg protein/kg) was made up according to the following formulation.
  • Protocol 4 groups of rats (5 animal/group) . Rats in the control group were fed lactalbumin diet (group 1) during the whole experiment and intragastrically intubated with saline for the last four consecutive days.
  • the second control (GNA) group were fed control diet to which GNA is added (0.7g/100g diet) for 6 days (pretreatment) and then intragastrically intubated with GNA (50-60mg GNA/rat/day) for the last four days.
  • Group 3 were treated exactly as Group 2 but on the last four days the rats were also intragastrically intubated with about 60mg of PHA/rat/day.
  • Group 4 were fed lactalbumin control diet throughout the whole experiment (6 days pretreatment + 4 days experimental period) and intubated for the last four days with about 60mg PHA/rat/day. Rats were killed, dissected and 10cm of their small intestine taken for bacterial counting. The numbers of lactose-fermenting (-57. coli) and non-lactose-fermenting coliforms and Lactobacillu ⁇ spp. were determined and expressed as numbers per gram of wet small intestinal tissue.
  • E. coli Eosin Methylene Blue Agar (Oxoid; Code CM69) was used for the bacteria subcultured from the MacConkey plates. Further confirmation was done with api 20E. Results: Compared with control values of about 10 8 E. coli/q wet proximal small intestinal tissue in the PHA- fed positive control rats, the number of E. coli was reduced to about 10 4 -10 5 /g wet tissue in the rats fed GNA before and after PHA treatment. GNA was particularly effective if, during the period of treatment with the two lectins, the rats' dietary input was restricted (1-2 g diet/rat/day, compared to 6 g/rat/day before the experiment) .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Botany (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Fodder In General (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Un grand nombre de micro-organismes (tels que les bactéries) peuvent entraîner des maladies ou d'autres états chez un animal hôte en se fixant à des récepteurs cellulaires hôtes au moyen de lectines ou d'adhésines spécifiques du sucre. Même des bactéries non pathogènes peuvent occasionner, par exemple, des colites non spécifiques, par ce moyen. Des lectines végétales, telles que l'agglutinine de Galanthus nivalis (AGN), peuvent être administrées pour entrer en concurrence notamment avec des adhésines bactériennes dans leur fixation sur les récepteurs contenant des sucres, de façon à traiter ou à prévenir les infections à médiation bactérienne. De telles lectines peuvent également être données à du bétail pour empêcher le développement des infections et elles constituent dans de tels cas une solution préférable à la pratique courante qui consiste à utiliser des antibiotiques.
PCT/GB1991/002236 1990-12-14 1991-12-16 Lectines probiotiques Ceased WO1992010204A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4502133A JPH06504533A (ja) 1990-12-14 1991-12-16 共生におけるレクチン

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9027185.9 1990-12-14
GB909027185A GB9027185D0 (en) 1990-12-14 1990-12-14 Probiosis

Publications (1)

Publication Number Publication Date
WO1992010204A1 true WO1992010204A1 (fr) 1992-06-25

Family

ID=10687026

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/002236 Ceased WO1992010204A1 (fr) 1990-12-14 1991-12-16 Lectines probiotiques

Country Status (6)

Country Link
EP (1) EP0561912A1 (fr)
JP (1) JPH06504533A (fr)
AU (1) AU9066891A (fr)
CA (1) CA2098305A1 (fr)
GB (1) GB9027185D0 (fr)
WO (1) WO1992010204A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991006311A1 (fr) * 1989-10-25 1991-05-16 Scottish Crop Research Institute Matiere antivirale

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991006311A1 (fr) * 1989-10-25 1991-05-16 Scottish Crop Research Institute Matiere antivirale

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Digestion, vol. 46, suppl. 2, 1990, (Basel, CH), A. PUSZTAI et al.: "Relationship between survival and binding of plant lectins during small intestinal passage and their effectiveness as growth factors", pages 308-316, see the abstract; page 315, left-hand column, line 7 - right-hand column, line 4 *
FEBS Letters, vol. 215, no. 1, May 1987, (Amsterdam, NL), E.J.M. VAN DAMME et al.: "Isolation and characterization of a lectin with exclusive specificity towards mannose from snowdrop (Galanthus nivalis) bulbs", pages 140-144, see the whole document (cited in the application) *
The Journal of Biological Chemistry, vol. 263, no. 2, 15 January 1988, (Baltimore, US), N. SHIBUYA et al.: "Binding properties of a mannose-specific lectin from the snowdrop (Galanthus nivalis) bulb", pages 728-734, see the abstract; page 733, right-hand column, lines 8-14 *
The Journal of Experimental Medicine vol. 146, no. 5, 1 November 1977, (New York, US), I.E. SALIT et al.: "Type I Escherichia coli pili: Characterization of binding to monkey kidney cells", pages 1182-1194, see the abstract; page 1187, lines 21-32; page 1192, lines 1-11 *

Also Published As

Publication number Publication date
CA2098305A1 (fr) 1992-06-15
GB9027185D0 (en) 1991-02-06
AU9066891A (en) 1992-07-08
JPH06504533A (ja) 1994-05-26
EP0561912A1 (fr) 1993-09-29

Similar Documents

Publication Publication Date Title
Andriole Synergy of carbenicillin and gentamicin in experimental infection with Pseudomonas
Greenberg Salmonella suppression by known populations of bacteria in flies
CN111909904B (zh) 一株巴氏杆菌噬菌体、其噬菌体组合物及其应用
EP1013283A2 (fr) Compositions pharmaceutiques et alimentaires contenant des transferrines et des agents antibactériens pour améliorer l'activité des dépenses immunitaires et pour le traitement d'infections
AU624356B2 (en) Bacterial preparation for prophylaxis and treatment of inflammatory processes and allergic diseases
RU2146526C1 (ru) Лечебно-профилактический препарат в твердой и мягкой формах и способ профилактики и лечения дисбактериоза и урогенитальных инфекций
CN106822092B (zh) 一种抑制嗜水气单胞菌感染的药物组合物
JP2023504887A (ja) サルモネラ菌ｉｉｉ型分泌系阻害剤の製造におけるミリセチンの使用
Plumb et al. Use of a potentiated sulfonamide to control Edwardsiella ictaluri infection in channel catfish (Ictalurus punctatus)
WO1992010204A1 (fr) Lectines probiotiques
CA2159359A1 (fr) Agent immunisant et anti-infection, renfermant deux ou plusieurs bacillus, du blanc d'oeuf et de l'ail
WO2019218986A1 (fr) Utilisation médicale de tectorigénine dans le traitement de l'entérite nécrotique du poulet
JP4695191B2 (ja) 胃液促進作用を有する新規微生物及びその分泌組成物
Rea et al. Comparative Efficacy of Substances Employed in Prevention of Intra-Peritoneal Adhesions
KR101762798B1 (ko) 아교 추출물을 포함하는 살모넬라균에 대한 항균용 약학적 조성물
JP2002265354A (ja) 抗ピロリ菌剤組成物
Felsenfeld et al. In vitro and in vivo tests with newer antibiotics against Endamoeba histolytica
Gupta et al. Comparative activity of anticestode drugs—praziquantel, niclosamide and Compound 77–6, against Hymenolepis nana
Dassanayake et al. Administration of a bolus formulation of baquiloprim and sulphadimidine to calves: plasma concentration-time profiles and efficacy in suppressing experimental pneumonic pasteurellosis
Santoso et al. Does glutamine supplementation increase radioresistance in squamous cell carcinoma of the cervix?
Jensen et al. Alterations in Type and Bactericidal Activity of Mouse Peritoneal Phagocytes after Intraperitoneal Administration of Endotoxin
CN117838676A (zh) 黄腐酚在制备抗水产养殖动物嗜水气单胞菌感染药物中的应用
Duncombe et al. Nippostrongylus brasiliensis infection in the rat: effect of iron and protein deficiency on the anthelmintic efficacy of mebendazole, pyrantel, piperazine, and levamisole.
SU1304736A3 (ru) Способ получени противоопухолевого средства
Gomez-Gil et al. Probiotics in the larval culture of aquatic organisms

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA FI JP NO US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2098305

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1992900831

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1992900831

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1992900831

Country of ref document: EP