WO1983004260A1 - Human leukocyte pepsin-like enzyme, and a therapeutic agent containing said enzyme as effective ingredient for treating allergic disorder, immune complex disease, and tumor - Google Patents

Human leukocyte pepsin-like enzyme, and a therapeutic agent containing said enzyme as effective ingredient for treating allergic disorder, immune complex disease, and tumor Download PDF

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Publication number
WO1983004260A1
WO1983004260A1 PCT/JP1982/000213 JP8200213W WO8304260A1 WO 1983004260 A1 WO1983004260 A1 WO 1983004260A1 JP 8200213 W JP8200213 W JP 8200213W WO 8304260 A1 WO8304260 A1 WO 8304260A1
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WO
WIPO (PCT)
Prior art keywords
enzyme
pepsin
human leukocyte
therapeutic agent
immune complex
Prior art date
Application number
PCT/JP1982/000213
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Haruo Ohnishi
Hiroshi Kosuzume
Yasuo Suzuki
Ei Mochida
Original Assignee
Mochida Pharmaceutical Co., Ltd.
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 Mochida Pharmaceutical Co., Ltd. filed Critical Mochida Pharmaceutical Co., Ltd.
Priority to PCT/JP1982/000213 priority Critical patent/WO1983004260A1/ja
Priority to AU84598/82A priority patent/AU8459882A/en
Priority to US06/498,506 priority patent/US4591504A/en
Priority to IT8348383A priority patent/IT1172264B/it
Priority to GB08314727A priority patent/GB2125046B/en
Priority to DE3319360A priority patent/DE3319360C2/de
Priority to AU15072/83A priority patent/AU547166B2/en
Priority to CA000429217A priority patent/CA1207262A/en
Priority to SE8303050A priority patent/SE8303050L/
Priority to BE0/210886A priority patent/BE896895A/fr
Priority to NL8301934A priority patent/NL8301934A/nl
Priority to FR8309006A priority patent/FR2527630B1/fr
Publication of WO1983004260A1 publication Critical patent/WO1983004260A1/ja

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6478—Aspartic endopeptidases (3.4.23)
    • C12N9/6481—Pepsins (3.4.23.1; 3.4.23.2; 3.4.23.3)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to an allergic disease, an immune complex disease, and a therapeutic agent for tumors, which comprises t-leukocyte pepsin-like enzyme and these enzymes as active ingredients.
  • An allergic disease is a reaction that causes a pathological process in the organism of antigen-antibody reaction, that is, a disease caused by an allergic reaction.
  • the mechanism of the onset of allergic disease is thought to be due to the following processes. That is, when a living body is exposed to a pathogenic antigen, the living body produces antibodies. When the antigen is invaded again while the antibody is being produced, an antigen-antibody reaction is evoked, and as a result, the chemical transfer substance is released from the cells, which impairs the ⁇ Therefore, the antigen-antibody complex is deposited in the umbilical cord and causes allergic symptoms and autoimmune diseases.
  • OMFI OMFI So-called allergic diseases caused by externally invading antigens such as bronchial asthma, dietary allergies and deprivation measles are classified into four types according to their symptoms or causes. That is, type I allergy (anaphylaxis type 1), which is caused by ⁇ ⁇ adhesive antibody and is characterized by increased vascular permeability and smooth muscle contraction, and is characterized by cell damage caused by the presence of complement.
  • type I allergic protein cystolytic type
  • antigen-anti-complex accumulates in the blood vessel wall, is attracted by the involvement of complement and polymorphonuclear leukocytes, and is characterized by an inflammatory reaction. Allergy (Ars type), which is characterized by the appearance of delayed type hypersensitivity reactions such as the tuberculin reaction caused by cellular immunity] y type allergic.
  • bronchial asthma involves types I, II, and IV, and it is thought that each of them, independently or in combination, induces an asthma attack. Be done.
  • the pathogenesis of these allergic diseases is considered as follows.
  • Antigens that have entered the body are processed by macrophages,
  • Antigen information is transmitted to the T cell-B cell line.
  • the informed B cells produce immune globulin (predominantly I 9 E in type I allergens, predominantly I g G in ⁇ -type and ⁇ -type allergies), and Among them, IgE antibody is fixed to basophils in bloodstream or obesity deer in gill, and a sensitized state is established. After that, the invading antigen is combined with the antibody fixed to the alveolar cell, and the histamine, SI ow, is released from these cells. It releases chemical substances such as reacting substance of anaphyla is (SRS-1A).
  • the released chemical mediators cause allergic symptoms such as erythema due to the contraction of smooth muscles or increased permeability of capillaries, edema or increased glandular cell secretion.
  • the Is G antibody binds to polynuclear leukocytes to form sensitization, and it is also considered that SRS-A is secreted as a chemi-cal mediator.
  • Anti-allergic agents can suppress either of these processes and thus achieve their therapeutic goals.
  • xanthine drugs 3 receptor stimulants or steroides have been used for the treatment of asthma, but these have unfavorable side effects. It is often accepted. For example, in xanthine-based drugs and receptor stimulants, it has been reported that they have heart palpitations and tachycardia. Furthermore,
  • Steroids have side effects such as the development of gastrointestinal ulcers or the combination of bacterial infections.
  • antihistamines are not effective against asthma attacks and may make it difficult to pump airway secretions, thus exacerbating asthma.
  • immune complex disease is a well-known name for the complex of various antigens and antibodies, that is, a disease caused by immune complexes. ..
  • the pathogenesis of immune complex disease is complicated and there are many unclear points.
  • Nanechi which is affected by bacteria, virus infection, etc.
  • Antibodies are produced against these antibodies
  • Vascular permeability is enhanced by releasing vascular plowing substances such as
  • polynuclear leukocytes are concentrated at the deposition site of the immune complex.
  • the decrease in complement value and the decrease in complement value are closely related to each other.
  • the complex is also associated with the blood coagulation system, and is a protein for the impaired ⁇ ⁇
  • ⁇ 'ItO Immunosuppressive agents such as drugs and anti-inflammatory agents, or anticoagulants or antiplatelet agents to improve abnormalities of the coagulation / fibrinolytic system produced in blood vessels are used.
  • drugs have weak effects and strong side effects, they do not always provide satisfactory therapeutic effects, and therefore they are safe and highly effective drugs.
  • an antitumor agent has been developed with an extremely large number of drugs. These antitumor agents are roughly classified into the following two types. In other words, it is the first type of cytotoxin, and its action directly suppresses the growth of tumors.
  • the selective toxicity to cells is not sufficient, and it also exerts a toxic effect on normal cells in the living body.
  • the tumor was derived from the normal cells of the patient.
  • the present inventors have found that allergic diseases, immune complex diseases and tumors
  • Peptin-like enzyme present in human leukocytes
  • Ten (Hereinafter, abbreviated as human leukocyte pepsin-like enzyme) has a strong anti-allergic effect, significantly suppresses various immune complex diseases, and has an excellent anti-tumor effect. Then, the present invention has been completed.
  • the human leukocyte pepsin-like enzyme is also present in the hemorrhagic leukemia cells H-160 strain treated with a differentiation inducer such as actinomycin D in human leukocytes. These cells are used for the purification of proteins from homogenized ⁇ -neutralized supernatants, such as common methods such as salting out, adsorption chromatographic methods using inorganic adsorbents, ion exchange laterals. This can be achieved by appropriately combining ion-exchange chromatographic graphs with fats and gel chromatographic graphs with molecular sieving effect.
  • culture of cells in which cancer cells are fused with pepsin-like enzyme-producing cells such as white blood cells, or genetic engineering techniques, for example, human white blood cell pepsin-like enzyme messenger RNA. It is possible to obtain a large amount by preparing a complementary DNA by reverse transcriptase, and incorporating this DNA into Escherichia coli, etc.
  • Airway constriction was significantly suppressed by the administration of 5 rag / kg 2 3 human leukocyte pesin-like enzyme.
  • Experimental example 1 3 Masugi nephritis inhibitory effect
  • Nebulitis was induced by intravenously injecting 5 mlZ kg intravenously. After nephritis was induced, blood and urine were collected at regular intervals to measure serum immune complex levels and urinary protein levels.
  • the human leukocyte pepsin-like enzyme was intravenously injected once a day after administration of the anti-renal antibody, and the inactivated human leukocyte pepsin-like enzyme was administered weekly as a control. The results are shown in Figures 2 and 3.
  • the amount of urinary protein in each mouse was measured using a test strip (combi-stem), and the results are shown in Fig. 4.
  • human leukocyte pepsin-like enzyme significantly suppressed the increase in urinary protein, the cell infiltration at 32 weeks of age was also mild, and the survival rate at 50 weeks of age was A high value was observed in the group treated with the white blood cell vesicin-like enzyme, and suppression of spontaneous renal lesions of mouse was observed by the human leukocyte pepsin-like enzyme.
  • mice were transplanted subcutaneously into the dorsal area of the back of the mouse, and two weeks later, intravenously administered t leukocyte pepsin-like enzyme twice a day for 18 days. On day 18 of the administration of human leukocyte pepsin-like enzyme, a tumor was excised and its weight was measured. The results are shown in Table 5.
  • control group 1.3 4 ⁇ 0 .1 0 human leukocyte pep 0.3 0.3 0.7 6 ⁇ 0.1 2 * syn-like enzyme administration group 3.0 0.6 6 ⁇ 0 .1 3 ⁇
  • the human leukocyte pepsin-like enzyme which is an active ingredient of the therapeutic agent of the present invention, suppresses IgE antibody production, and has a clear therapeutic effect on experimental asthma. showed that.
  • this human leukocyte pepsin-like enzyme also exhibited a strong antitumor effect.
  • this white blood cell pepsin-like enzyme is a protein derived from human, it causes serious side effects such as anaphylactic shock due to its antigenicity. It is considered to be a clinically extremely useful drug against allergic diseases such as asthma, various immune complex diseases and various tumors. It is.
  • Figure 1 is a graph showing the results of Experiment 1 and Figures 2 and 3 are graphs showing the results of Experimental Example 13.
  • Fig. 4 is a graph showing the results of urinary protein amount measurement in each experiment. The urinary protein amount was measured by the coloration of the test paper, and (1) was 0, (+). The mean value of each group is represented by an index with 1, (+ +) as 2, (+ + +) as 3, and (+ + + +) as 4.
  • t Leukocyte pepsin-like enzyme allows the supernatant of human leukocyte homogenate to pass through the DEAE-cellulosic column equilibrated in 0. Acetate buffer (PH 5.3). Then, after adsorbing the human white blood cell pepsin-like enzyme, it is eluted in a peripheral buffer containing 0.5 M sodium chloride. After the eluate was condensed, it was further purified by a gel chromatographic graph by using Sephadex G—100, which was swollen in 0, 9% physiological saline. You can get more from what you do. This white blood cell pepsin-like enzyme is called Sephadex G.
  • this human leukocyte pepsin-like enzyme exhibits high hydrolytic activity against hemoglobin in the acidic region of pH 7.0 or lower, and its optimum pH is 2.0 to 3. It is 5.
  • the therapeutic agent of the present invention is usually administered as an injection, intravenously, subcutaneously, intramuscularly, intraarticularly, or locally in a tumor, but it may also be used as an oral agent, an inhalant, or a rectal suppository. it can.
  • the therapeutic dose of white blood cell pepsin-like enzyme is 1 to 100 mg / day, preferably 50 to 500 mg, depending on age, symptoms, or usage. It can be increased or decreased as appropriate.
  • the human leukocyte pepsin-like enzyme can be so-called manufactured into a pharmaceutical preparation by a conventional method together with an optional conventional pharmaceutical carrier or excipient.
  • a freeze-dried preparation to be dissolved upon use, an injection solution, or a sustained-release preparation to maintain the effective concentration.
  • the drug for oral administration may be capsules, tablets, granules, powders or oral liquid preparations, but it is preferable to use liposome inclusion bodies in order to promote absorption.
  • freeze-dried agents as inhalants and rectal suppositories as rectal administration agents.
  • examples of the present invention will be shown.
  • HL-60 leukemia cells treated with actinomycin D "10 11 cells were suspended in 1 ⁇ 0.9% saline and disrupted with a homogenizer. The supernatant obtained by centrifugation at 30 rpm for 30 minutes was desalted and concentrated using an ultracontractor (Millipore, Diaflo-type 1022). Equilibrated with phosphate buffer (PH 7.0); adsorbed on DEAE cellulose column (10 X 50 cm) and with buffer 4 containing 0.1 M Na CI. After washing, the active fraction was obtained by elution in a buffer containing 0.4 M Na CI, and then equilibrated with 0.9% saline containing no ripening substance.
  • Human Bok leukocytes 1 0 10 a 1 96 ⁇ ⁇ on X- 1 0 0, 1 0 m M Ba Nazarite complex, 3 ffl M acetate Ma Gune shea c beam, 1 0 m N a CI, 5% tio sugar Crushed in a Teflon homogenizer in 20 0 ⁇ ⁇ ⁇ ⁇ ⁇ ( ⁇ ⁇ 7.4) and then centrifuged to obtain a polymer fraction. .. Then After extracting m-RNA with phenol, kill it with ethanol and add 0.5% SDS, 0.01 MEDTA and
  • 0.2 M potassium lysine hydrochloric acid solution (PH 9.0) containing 50 MN a CI was added, and the mixture was incubated at 70 for 3 minutes.
  • This m-RNA solution was adsorbed on an oligo (dT) cellulosic column, washed, and washed, and then washed with 10 la N sodium chloride hydrochloric acid solution containing 0.5% SDS and iMEDTA (H 7.4. ), Elute the m-RNA containing Poly A, and fractionate this IB--NA by ⁇ > 5 to 25% sucrose density gradient method, and use oocytes of Cuba frog.
  • the protein synthesis system was used to search for pepsin-like enzyme S5 — RNA activity, and an active fraction was obtained.
  • the pepsin-like enzyme in-R.NA59 obtained in this manner was added to 1 Hg of oligo (dT) 10 , 5 ffl M mercaptoethanol and 0.5 ifl. M d ATP, d TTP, d G ⁇ ⁇ , d CTP, 40 units of reverse transcriptase (AV-RT) in 40 in M sodium chloride buffer (PH 7.5) in 100 UI In addition, at 42, it was 90 minutes. Next, RNA was removed by deproteinization and alkaline treatment to obtain primary DNA. Then, when the above-mentioned computer DNA was obtained, it was inspected at the same time as the medium (it does not include the human oligo (d T) 10 ), and the double decoupling was performed. A single primary DNA was obtained. This double-stranded computer DNA was loaded with 0.25 units of Nuclease S.
  • E. coli plasmid PBR 3 2 2 DNA was treated with 0.25 units of EcoRI and 37 for 20 hours and then treated with 17.5 units of exonuclease. After incubating for 90 minutes, the conditions and frequency of preparation of the above-mentioned decacia dnadenine strand DNA (however, d TTP instead of d ATP were used). , Which contains deoxyribonucleotide chain DNA.
  • Example 1 4 Dissolve human leukocyte pepsin-like enzyme i g in 1 OO BI of physiological saline, and aseptically filter using a membrane filter. Fill 1 nil of the filtrate into a sterilized glass container, freeze-dry, and stopper tightly to make a freeze-dried powder formulation.
  • Example 1 4 Dissolve human leukocyte pepsin-like enzyme i g in 1 OO BI of physiological saline, and aseptically filter using a membrane filter. Fill 1 nil of the filtrate into a sterilized glass container, freeze-dry, and stopper tightly to make a freeze-dried powder formulation.
  • Example 1 4 Dissolve human leukocyte pepsin-like enzyme i g in 1 OO BI of physiological saline, and aseptically filter using a membrane filter. Fill 1 nil of the filtrate into a sterilized glass container, freeze-dry, and stopper tightly to make a freeze-dried powder formulation.
  • Egg yolk lecithin, cholesterol and diacetylphosphite were mixed in a molar ratio of 7 to 2 to 1, and 100 iag of the mixture was dissolved in 12.5 m I of cro-alpha form, and the flask wall was mixed. A thin film was prepared. This film was mixed with 25 ml of a phosphate buffer solution containing 100 mg of human leukocyte pepsin-like enzyme to prepare a dispersion liquid. After sonication, centrifuge at 100 000 g and suspend the obtained precipitate in 3 ⁇ of physiological saline. Get the drug product

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PCT/JP1982/000213 1982-05-31 1982-05-31 Human leukocyte pepsin-like enzyme, and a therapeutic agent containing said enzyme as effective ingredient for treating allergic disorder, immune complex disease, and tumor WO1983004260A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PCT/JP1982/000213 WO1983004260A1 (en) 1982-05-31 1982-05-31 Human leukocyte pepsin-like enzyme, and a therapeutic agent containing said enzyme as effective ingredient for treating allergic disorder, immune complex disease, and tumor
AU84598/82A AU8459882A (en) 1982-05-31 1982-05-31 Human leukocyte pepsin-like enzyme, and a therapeutic agent containing said enzyme as effective ingredient for treating allergic disorder, immune complex disease, and tumor
US06/498,506 US4591504A (en) 1982-05-31 1983-05-26 Human leucocyte pepsin-like enzyme as a therapeutic agent for treating allergic disorders and immune complex diseases
IT8348383A IT1172264B (it) 1982-05-31 1983-05-27 Enzima simile a pepsina da leucocito umano,procedimento per prepararlo,e composizione terapeutica che lo continene come ingrediente attivo
GB08314727A GB2125046B (en) 1982-05-31 1983-05-27 Human leucocyte pepsin like enzyme
DE3319360A DE3319360C2 (de) 1982-05-31 1983-05-27 Pepsinartiges Human-Leukozyten-Enzym und Verwendung desselben zur Behandlung allergischer Störungen, Immunkomplex-Erkrankungen und von Tumoren
AU15072/83A AU547166B2 (en) 1982-05-31 1983-05-30 Human leucocyte pepsin-like enzyme
CA000429217A CA1207262A (en) 1982-05-31 1983-05-30 Human leucocyte pepsin-like enzyme, method for preparation of the enzyme, and method and therapeutic agent for treating allergic disorders, immune complex diseases and tumors containing the same as an effective ingredient
SE8303050A SE8303050L (sv) 1982-05-31 1983-05-30 Pepsinliknande enzym fran humana leukocyter, forfarande for enzymets framstellning, samt terapeutiskt medel, innehallande enzymet som aktiv bestandsdel och avsett for behandling av allergisjukdomstillstand, immunkomplex
BE0/210886A BE896895A (fr) 1982-05-31 1983-05-31 Enzyme analogue a la pepsine leucocytaire humaine et compositions et agents therapeutiques qui la contiennent.
NL8301934A NL8301934A (nl) 1982-05-31 1983-05-31 Menselijk leukocyt pepsineachtig enzym, werkwijze voor het bereiden van het enzym, en werkwijze en therapeutisch middel voor het behandelen van allergiekwalen, immuuncomplexziekten en tumoren, in welk middel dit als werkzaam ingredient aanwezig is.
FR8309006A FR2527630B1 (fr) 1982-05-31 1983-05-31 Enzyme leucocytaire humaine de type pepsique, procede pour sa preparation et agent therapeutique la contenant

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PCT/JP1982/000213 WO1983004260A1 (en) 1982-05-31 1982-05-31 Human leukocyte pepsin-like enzyme, and a therapeutic agent containing said enzyme as effective ingredient for treating allergic disorder, immune complex disease, and tumor

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US (1) US4591504A ( )
AU (2) AU8459882A ( )
BE (1) BE896895A ( )
CA (1) CA1207262A ( )
DE (1) DE3319360C2 ( )
FR (1) FR2527630B1 ( )
GB (1) GB2125046B ( )
IT (1) IT1172264B ( )
NL (1) NL8301934A ( )
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Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5995221A (ja) * 1982-11-20 1984-06-01 Mochida Pharmaceut Co Ltd 食細胞機能調節作用を有する医薬組成物
ATE87214T1 (de) * 1987-09-30 1993-04-15 Mucos Emulsions Gmbh Verwendung katabolischer enzyme zur herstellung eines medikaments zum bekaempfen der erworbenen immunschwaeche (aids) und deren vorstadien (las, arc).
ES2038546B1 (es) * 1991-11-08 1994-02-16 Andromaco Lab Procedimiento de obtencion de un producto de naturaleza polipeptidica con actividad inhibidora de la hiperproduccion del factor de necrosis tumoral.
JP2711436B2 (ja) * 1995-02-22 1998-02-10 マルホ株式会社 アレルギー治療剤及びアレルギー対応食品

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2119872A1 (fr) * 1970-12-30 1972-08-11 Kuban Med I Im Krasnoi Armii Produit a base de pepsine,notamment pour le traitement des maladies s'accompagnant d'une insuffisance secretoire de l'estomac
US3796636A (en) * 1972-07-14 1974-03-12 Wilson Pharm & Chem Corp Process for preparing high activity pepsin
US4229540A (en) * 1979-07-02 1980-10-21 Cutter Laboratories, Inc. Hydrolase purified from human plasma

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT, Vol. 60, No. 2, 20 January 1964 (20.1.64) (Columbus, Ohio, USA), L.A. MOUNTER et al., "Proteases of Human Leukocytes", see column 1, Abstract No. 1987a, Blood, 1960, 15, 52-59. *
CHEMICAL ABSTRACT, Vol. 75, No. 25, 20 December 1971 (20.12.71) (Columbus, Ohio, USA), KOPITAR, M. et al., "Leukocyte Proteinases. II. Partial Purification of Proteinase Present in Cathepsin D Preparation", page 24, column 1, Abstract No. 147963Y, Euzymologia, 1971, 41(2), 129-139. *
Hakko to Kogyo, Vol. 38, No. 3, March 1980 (Tokyo), CHIBATA ICHIRO, TOSA TETSUYA, "Iryoyo Koso", p. 238-247. *

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GB2125046B (en) 1985-08-07
FR2527630A1 (fr) 1983-12-02
NL8301934A (nl) 1983-12-16
CA1207262A (en) 1986-07-08
AU8459882A (en) 1983-12-16
GB2125046A (en) 1984-02-29
IT8348383A0 (it) 1983-05-27
FR2527630B1 (fr) 1986-07-11
DE3319360A1 (de) 1983-12-01
BE896895A (fr) 1983-09-16
DE3319360C2 (de) 1986-10-09
SE8303050L (sv) 1983-12-01
US4591504A (en) 1986-05-27
AU1507283A (en) 1984-01-19
AU547166B2 (en) 1985-10-10
SE8303050D0 (sv) 1983-05-30
IT1172264B (it) 1987-06-18
GB8314727D0 (en) 1983-07-06

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