IE59806B1 - Tripeptide with immunostimulating activity - Google Patents

Tripeptide with immunostimulating activity

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Publication number
IE59806B1
IE59806B1 IE88187A IE88187A IE59806B1 IE 59806 B1 IE59806 B1 IE 59806B1 IE 88187 A IE88187 A IE 88187A IE 88187 A IE88187 A IE 88187A IE 59806 B1 IE59806 B1 IE 59806B1
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IE
Ireland
Prior art keywords
arg
tripeptide
ala
cells
formula
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IE88187A
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IE870881L (en
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Ellem Ind Farmaceutica
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Application filed by Ellem Ind Farmaceutica filed Critical Ellem Ind Farmaceutica
Publication of IE870881L publication Critical patent/IE870881L/en
Publication of IE59806B1 publication Critical patent/IE59806B1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0815Tripeptides with the first amino acid being basic
    • C07K5/0817Tripeptides with the first amino acid being basic the first amino acid being Arg
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The tripeptide Arg-Ala-Arg, synthetized by conventional solution methods, and its salts display immunostimulating activity both on maturation of immature T cells and on T cell function.

Description

This invention relates to a peptide having interesting physiological activity.
Thus, in accordance with one aspect, the invention provides a tripeptide comprising residues of L-alanine (Ala) and L5 arginine (Arg), and having the formula Arg-Ala-Arg and salts thereof.
We have found that the tripeptide according to the invention, as well as its pharmaceutically acceptable salts, exhibits interesting physiological activity. In particular, we have found that the tripeptide produces an immunostimulating activity by both stimulating the maturation of immature Tcells and T-cell function. We therefore believe that the tripeptide may be useful in the treatment of immunodeficient conditions such as primary or secondary immunodeficiency.
Thus, in accordance with a further aspect, the invention provides a pharmaceutical composition comprising a tripeptide of formula Arg-Ala-Arg or a physiologically acceptable salt thereof in association with a pharmaceutical carrier or excipient.
Pharmaceutical compositions according to the invention may be in a form suitable for parenteral, oral or rectal administration. Examples of such forms include solutions, emulsions, suspensions, powders, tablets, capsules, coated tablets, syrups, suppositories and the like.
It will be appreciated that salts of the tripeptide for use in medicine will be physiologically acceptable. Other salts may, however, be useful in the preparation of the tripeptide or the physiologically acceptable salts thereof.
The tripeptide and its salts according to the invention may be prepared by generally conventional techniques. Thus, for example, the tripeptide may be prepared from corresponding dipeptides, preferably as their appropriately protected derivatives, which dipeptides themselves may be prepared by coupling appropriate amino acids or protected derivatives thereof.
Thus, in a further aspect, the invention provides a process for the preparation of the tripeptide or salt thereof according to the invention which comprises a) reacting a compound of formula Ala-Arg (or a protected derivative thereof) with L-arginine (or a protected derivative thereof); or b) reacting a compound of formula 20 Arg-Ala (or a protected derivative thereof) with L-arginine acid (or a protected derivative thereof); and, where appropriate, subsequently removing protecting groups.
It is known from the literature that L-alanine is important 25 for the function of T lymphocytes, as it has been found essential that these cells can respond in vitro to mitogenic stimuli (Rotter V. et al.: J.Immunol. 123, 1726, 1979).
Moreover, L-alanine is also essential for the growth in vitro of lymphocytes (Nordlind K. et al.: Int. Archs Allergy appl.
Immunol. 59, 215, 1979).
We have found, however, that this amino acid exhibits only a very faint immunostimulating activity, as shown in an in vitro test of Thy 1.2 induction on immature T cells from normal mice.
L-arginine has also been reported to have an immunostimulating activity both in vitro and in vivo, particularly in injured and stressed animals (Barbul A. et al.: J.Surg. Res. 29, 228, 1980; J.Parenteral Enteral Nutr. 4,446,1980; ibid. 5.492.1981), and in experimentally induced tumors (Rettura G.: J.Parenteral Enteral Nutrition 3,409, 1979). In our tests on Thy 1.2 induction, however, L-arginine also only shows a scant,, although statistically significant, activity.
We have compared the activity of the tripeptide of the invention with that of a mixture of the two single amino acids in a ratio of two moles of Arg to one mole Ala. The tripeptide has been found to be far more active than the mixture of the two amino acids. For example, it induces Thy 1.2 in 13% of cells (P <0.0l) compared to only 5% (statistically not significant) with the mixture.
The tripeptide according to the invention may be prepared in accordance with the following non-limiting example:Example (A) NOj I Boc-Ala-Arg-OBe (I) (where Boc represents a represents a benzyl group) t-butoxycarbonyl group, and Be To Boc-Ala (0.1 mole) dissolved in methylene chloride and cooled to 0°C was added isobutyl chloroformate (0.1 mole) with stirring while lowering the temperature at -15°C. After stirring the reaction mixture for minutes to this temperature, a precooled solution of NGnitro-arginine-benzyl ester di-p-tosylate (0.1 mole) and Nmethylmorpholine (0.2 moles) in dimethylformamide was added slowlv and the reaction mixture then stirred overnight. / Solvents were removed under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate solution was successively washed with water, IN hydrochloric acid, water, % sodium bicarbonate solution and water. It was dried over sodium sulphate and the solvent was removed under reduced pressure. A syrupy product is obtained. TLC, chloroform: methanol: acetic acid (90:8:2), 95% pure. Yield 80%.
(B) Compound (I) was deprotected with a 50% trifluoroacetic acid (TFA)-methylene chloride mixture (1:1), 10 ml per gram, for half an hour. It was then evaporated under reduced pressure, triturated with ether, filtered, washed with ether and dried in vacuo. Yield 98%.
(C) The TFA-Ala-Arg-OBe product of (B) was neutralized with Nmethylmorpholine and coupled to Z3-Arg (where Z represents a benzyloxycarbonyl group) in a dimethylformamidetetrahydrofuran mixture using N-methylmorpholine and isobutyl chloroformate and worked up as in (A) . Yield 60%. TLC, chloroform: methanol (92:8), one major spot.
The tripeptide was then hydrogenated in an acetic acid-watermethanol mixture in the presence of Pd/C until completion. It was filtered from the catalyst and the filtrate was evaporated in vacuo. * The product tripeptide was purified by counter current distribution using n-butanol: acetic acid: water (4:1:5) Yield 50%. TLC, butanol: acetic acid: water: pyridine (32:6:22:20), one major spot. HPLC 97%.
Chemical Characteristics of Tripeptide Molecular Weight: 401.49 Optical Rotation: [X]2d = 3.69, (c=l, acetic acid) HPLC Analysis: the tripeptide has been analyzed by ion-pairing HPLC, according to the following separation conditions; Eluent; NaH2 PO4 0.05M pH 4.3 + sodium dodecylsulphate 5 x 10' 4 M, methanol; 50:50.
Flow rate; 1 ml/min Detection: 225 nm Injection volume: 20 μΐ Samples 20 gg Column; u Bondapack Cl8 (waters), 300 x 3.9 mm The following instrumentation was used: Liquid chromatograph: SERIES 4 (Perkin Elmer) Injection valves Reodyne mod. 7125-075, with a 20 μΐ loop Detector; Spectrophotometer LC 95 (Perkin Elmer) Computing integrator: Data Station 3600 (Perkin Elmer) The figure of the accompanying drawing shows the HPLC profile of the tripeptide.
Resistance to In Vitro Simulated Gastric environment The tripeptide is resistant to an in vitro simulated gastric environment. In this study the simulated gastric juice USP XXI (HCI + pepsin) was used at 37°C for 5 hrs.
BIOLOGICAL ACTIVITY l.A. In Vitro Induction of Thy 1.2 Antigen The capacity of Arg-Ala-Arg to induce in vitro differentiation of mouse T cell precursors into lymphocytes expressing T cell markers has been tested by assessing the induction of Thy 1.2 membrane antigen.
MATERIAL AND METHODS MICE: 8 week-old athymic (nu/nu) mice outbred on C3H/He 5 background, maintained under specific pathogen-free conditions were used.
PREPARATION OF THE CELLS: spleens were aseptically removed, minced and passed through a fine-mesh stainless steel sieve into Hank’s balanced salt solution (HBSS) (Gibco Ltd., Paisley, Scotland). Splenocytes, washed and resuspended in 199 medium (Gibco Ltd.,) supplemented with 1% BSA (Boehringer Mannheim) and gentamvcin (100 Mg/ml), were incubated for 45 minutes in equilibrated nylon wool columns according to the method of Julius et al. (Eur. J. Immunol. 3, 645, 1973). The effluent cell populations enriched with precursor T cells, were used in the bioassay.
INDUCTION BIOASSAY: 0.5xl06 effluent cells in 0.1 ml medium were incubated at 37°C for 18 hours with 0.1 ml of tripeptide or medium alone. Cultures were duplicated. At the end of the incubation period, the cells were washed with 0.87% ammonium chloride to lyse red cells and then with HBSS.
The induction of membrane Thy 1.2 antigen was determined by a direct immunofluorescence test.
DIRECT IMMUNOFLUORESCENCE: the cells were incubated at 4°C for 20 minutes with fluorescein-conjugated monoclonal antibody (Bio - Yeda) at 1:200 dilution. The mixture was centrifuged at 300 g for 5 minutes, washed twice in HBSS and then suspended, for counting on a fluorescence microscope (Leitz Orthoplan*). The percentage difference of fluorescing cells between cultures with and without tripeptide indicated the inducing activity of the product.
RESULTS As shown in the Table below, the tripeptide induces the appearance of the marker Thy 1.2 on immature T cells with an optimum response at 10 Mg/ml. The dose-response relationship curve is bell-shaped, as both lower and higher concentrations of the peptide provoke a smaller induction.
PEPTIDE % THY 1.2+CELLS CONCENTRATION (Mg/ml) MEAN ± S.E. DIFFERENCE 0 11 + 1.6 0.0001 13 ± 3.9 + 2 0.001 25 ± 5 4- 14 0-01 36 ± 3.7 4- 25 0.1 36 ± 5.4 4- 25 1 41 ± 1.6 + 30 10 48 ± 2.2 4- 37 20 33 ± 3.3 4- 22 50 29 ± 3.3 4- 18 100 19 ± 1.7 4- 8 200 19 ± 4.5 4- 8 l.B In Vivo Induction of Thy 1.2 Antigen ELS2 (i.e. the tripeptide according to the invention) was administered in varying concentrations and by different routes on 4 consecutive days after which the mice were rested for 24 hrs. Their spleens were then removed and cells were examined «Registered Trade Mark for expression of the Thy 1.2 antigen by fluorescence. The control mice were given Medium 199 (M 199) , the medium in which the drug was dissolved. The mice had an average weight of about 24 g.
RESULTS % THY 1.2+ CELLS Oral i.p.
Control 2% 4% ELS 2 42 Mg/kg 3% 4% ELS 2 420 Mg/kg 6% 7% ELS 2 1055 Mg/kg 17% 19% ELS 2 2110 Mg/kg 16% 17% ELS 2 4220 Mg/kg 18% 17% ELS 2 8440 Mg/kg 17% 20% The data show that ELS2 is able to induce maturation of splenocytes after both oral and i.p. administration.
The optimal dosage is 1055 Mg/kg, since with higher dosages plateau response is observed. 2. In Vitro Stimulation of Lymphokine Production MATERIAL AND METHODS: PREPARATION OF HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS (P3MC) . Peripheral blood is obtained from healthy volunteers by veni-puncture. The red blood cells are separated from white cells on Ficoll*-Hipaque gradients. The buffy coat (PBMC) is removed and washed, and the cells are resuspended at lxlO6 cells/ml in RPMI 1640, supplemented with 1% panicillin/streptomycin, 1% glutamine and 1% heat inactivated fetal calf serum (FCS, 56°C 3 0 min) .
«Registered Trade Mark PREPARATION OF GROWTH FACTOR PBMC at lx 106 cells/ml in 1% heat inactivated FCS is incubated with and without Phytohemagglutinin (PHA) at 0.75% concentration v/v. The peptide to be tested is added at a concentration of 1 Mg/ml to appropriate cultures. The incubation period is 18-24 hrs., at 37°C in a humidified atmosphere. The cultures are then filtered through 0.22 mM filters and supernatants are examined for the presence of growth factors.
MEASUREMENT OF GROWTH FACTORS IN SUPERNATANTS A. Test cells The B cells used to test for the presence of B cell growth factor (BCGF) are long term cultured cell lines, maintained on BCGF, and are EBV negative. These cells are grown in serum free medium using Nutridoma (Boehringer Mannheim Biochemicals), and do not respond to IL-2.
The T cells used to test for the presence of IL-2 are freshly isolated. They are initially stimulated with PHA (0.75%) and are maintained in culture for at least 10 days prior to use (to reduce background and establish their dependence on IL-2).
B. Preparation of Test cells for Use in Assay. 1. B cells are usually used 4 days after last feeding with BCGF. They are washed 4 times in RPMI 1640 to remove any remaining BCGF, and adjusted to 15x10’ cells/ml in RPMI 1640 and Nutridoma (at 1% final concentration). 2. T cells are used 4 days after last feeding with IL-2. They are washed 4 times and adjusted to 50xl02 * 4 cells/ml in RPMI 1640 with 5% FCS.
C. Assay Procedures 1. Long term cultured B cells are incubated with various ; concentrations of supernatant from PBMC cultures, in 96 flat bottom microtiter plates. Each well has a total volume of 200 μΐ, consisting of 100 μΐ of B cells (15x10’ cells) and 100 μ! of supernatant. We examine the efficacy of our test 3 cells by incubating them with various concentrations of purified BCGF (Cellular Products, Inc. Buffalo, N.Y.).
The cultures are incubated for 24 hrs., after which 1 μθΐ of 10 [’H-Tdr] is added and then incubated additionally for 12 hrs.
The cultures are then harvested and counted in a scintillation counter. 2. T cells are incubated in flat bottom wells. The total volume in each well is 200 μΐ, which includes 50x10’ T cells/well. The incubation period is 72 hrs which includes 12 hours of labelling with [’H-Tdr].
RESULTS 1) GROWTH FACTOR PRODUCTION EXPERIMENT 1 BCGF % ACTIVITY SUP. (C.P.l M.) Sunt. from 3.05 6.25 12.5 25 50 PBL + PHA 424 1026 1674 3172 8392 P3L + PHA + ELS2 2772 4616 6336 8186 9818 ( (z TCGF ACTIVITY (C.P.M.) % SUP» PBL + PHA 542 192 224 564 1144 PBL + PHA + ELS 2 384 718 1832 4028 8338 EXPERIMENT 2 BCGF ACTIVITY (C.P.M .) % sun. Swot. from 3.125 6.25 12.5 25 50 PBL + PHA 1369 2187 2894 4876 8104 PBL + PHA + ELS 2 2690 4214 7442 8730 11754 TCGF ACTIVITY (C.P.M ·) % Sup. PBL + PHA 1482 3146 4322 7184 9012 PBL + PHA 4- ELS 2 2968 6220 9354 12014 12984 3. Effect on RNA Synthesis The effect of ELS2 on RNA synthesis in human T-cells observed by incorporation of 3H~uridine. was Results obtained (Counts per minute, CPM) after 24 hrs incubation: T 3732 T + PHA 20752 of ELS2 Concentration ug/ml 0.1 1 10 20 T + ELS2 4741 4834 5086 5130 25 T 4- ELS 2 + PHA 31000 31413 32706 31494 4» Effect on DNA Synthesis The effect of ELS2 on DNA synthesis in human T-cells was observed, by incorporation of 3H~thymidine.
Results obtained (Counts per minute, CPM) after 3 days oi incubation: T 154 T + PHA 6076 ELS2 Concentration ug/ml T + ELS2 T 4- ELS2 4- PHA 0.01 152 5758 0.1 166 6477 190 7548 234 12317 , In Vitro increase of cell number The tripeptide, added to cultures of either T lymphocytes or mixtures of T and B lymphocytes every fourth day at a concentration of 5 μ/ml for a period of 30 days, is able to increase cell number with a maximum of 4- 50% with respect to control cultures, observed between day 10 and day 15 of the experiment.
TOXICOLOGICAL STUDIES ACUTE TOXICITY Acute toxicity studies carried out on mice and rats have shown that up to a dose of 1000 mg/Kg i.m. the tripeptide is totally devoid of toxic effects.
TOLERABILITY Studies on rabbits and mice have shown that the product, at a dosage of 100 mg/Kg respectively i.v. and i.p., does not cause any hemodynamic modification and behavioral effect.
Particularly, pentobarbital-induced sleeping time shows only a slight increase.
ALLERGY-INDUCING ACTIVITY The product, at a dosage of 100 mg/Kg i.m. does not induce any sensitization phenomena in the guinea-pig.
SALTS OF THE TRIPEPTIDE The above mentioned tests were carried out with an acetate salt of the tripeptide. However, it is believed that similar results would be obtained using other salts, for instance the trlfluoroacetate, hydrochloride or sulfate salts.

Claims (10)

1. A tripeptide comprising residues of L-alanine (Ala) and L-arginine (Arg) , and having the formula ¢. Arg-Ala-Arg
2. A tripeptide according to claim 1 in the form of an acetate, trifluoroacetate, hydrochloride or sulfate salt.
3. A pharmaceutical composition comprising a tripeptide of formula 10 Arg-Ala-Arg or a physiologically acceptable salt thereof in association with a pharmaceutical carrier or excipient.
4. A composition according to claim 3 in a form suitable for parenteral, oral or rectal administration. 15 5. Use of a tripeptide of formula Arg-Ala-Arg or a physiologically acceptable salt thereof for the preparation of a medicament for immunostimulation.
5. Appropriate, subsequently removing protecting groups. 5 and salts thereof.
6. Use according to claim 5 for the preparation of a 20 medicament for the treatment of immunodeficiency.
7. A process for the preparation of a compound as defined in claim 1 which comprises a) reacting a compound of formula J Ala-Arg (or a protected derivative thereof) with L-arginine (or * a protected derivative thereof); or (to) reacting a compound of formula Arg-Ala (or a protected derivative thereof) with L-arginine acid (or a protected derivative thereof); and, where
8. A process according to claim 7 substantially as herein described.
9. A compound according to claim 1 substantially as herein specifically disclosed.
10. Dated this 6th day of April, 1987
IE88187A 1986-04-09 1987-04-06 Tripeptide with immunostimulating activity IE59806B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IT20027/86A IT1188646B (en) 1986-04-09 1986-04-09 TRIPEPTIDE WITH IMMUNOSTIMULANT ACTIVITY

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IE870881L IE870881L (en) 1987-10-09
IE59806B1 true IE59806B1 (en) 1994-04-06

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JP (1) JPH0645637B2 (en)
KR (1) KR870010080A (en)
AR (1) AR242799A1 (en)
AT (1) ATA88387A (en)
AU (1) AU597048B2 (en)
BE (1) BE1000263A4 (en)
CA (1) CA1322715C (en)
CH (1) CH676467A5 (en)
DE (1) DE3712050A1 (en)
ES (1) ES2003043A6 (en)
FR (1) FR2597107B1 (en)
GB (1) GB2189491B (en)
GR (1) GR870568B (en)
IE (1) IE59806B1 (en)
IT (1) IT1188646B (en)
NL (1) NL8700827A (en)
SE (1) SE8701457L (en)

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RU2058553C1 (en) * 1994-03-18 1996-04-20 Иван Николаевич Головистиков Method of estimation of human immune status suppressive link
RU2056852C1 (en) * 1994-03-18 1996-03-27 Иван Николаевич Головистиков Agent for treatment of autoimmune diseases with suppressor immunodeficiency and a method of autoimmune diseases treatment
GB0130285D0 (en) * 2001-12-19 2002-02-06 Astrazeneca Ab Chemical process
GB0130286D0 (en) * 2001-12-19 2002-02-06 Astrazeneca Ab Chemical process

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US3778426A (en) * 1970-12-16 1973-12-11 Research Corp Therapeutically useful polypeptides
US4215112A (en) * 1979-03-14 1980-07-29 Ortho Pharmaceutical Corporation Tripeptides and methods

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Publication number Publication date
IE870881L (en) 1987-10-09
IT1188646B (en) 1988-01-20
IT8620027A1 (en) 1987-10-09
IT8620027A0 (en) 1986-04-09
JPH0645637B2 (en) 1994-06-15
ES2003043A6 (en) 1988-10-01
GB2189491A (en) 1987-10-28
SE8701457L (en) 1987-10-10
CA1322715C (en) 1993-10-05
SE8701457D0 (en) 1987-04-07
AR242799A1 (en) 1993-05-31
AU7118287A (en) 1987-10-15
FR2597107B1 (en) 1991-02-22
FR2597107A1 (en) 1987-10-16
ATA88387A (en) 1996-05-15
BE1000263A4 (en) 1988-09-27
JPS62267296A (en) 1987-11-19
AU597048B2 (en) 1990-05-24
KR870010080A (en) 1987-11-30
GB8708492D0 (en) 1987-05-13
GB2189491B (en) 1990-02-21
DE3712050C2 (en) 1992-02-13
GR870568B (en) 1987-08-12
DE3712050A1 (en) 1987-10-15
NL8700827A (en) 1987-11-02
CH676467A5 (en) 1991-01-31

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