EP0409994A1 - Active vitamin d for chronic hepatitis treatment - Google Patents

Active vitamin d for chronic hepatitis treatment

Info

Publication number
EP0409994A1
EP0409994A1 EP90900979A EP90900979A EP0409994A1 EP 0409994 A1 EP0409994 A1 EP 0409994A1 EP 90900979 A EP90900979 A EP 90900979A EP 90900979 A EP90900979 A EP 90900979A EP 0409994 A1 EP0409994 A1 EP 0409994A1
Authority
EP
European Patent Office
Prior art keywords
chronic hepatitis
dihydroxyvitamin
vitamin
active vitamin
active
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.)
Withdrawn
Application number
EP90900979A
Other languages
German (de)
French (fr)
Inventor
Choju Aoki
Masanori Hirano
Hideki Horiuchi
Keiji Komariya
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.)
Teijin Ltd
Original Assignee
Teijin 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 Teijin Ltd filed Critical Teijin Ltd
Publication of EP0409994A1 publication Critical patent/EP0409994A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems

Definitions

  • the present invention relates to a pharmaceutical preparation for chronic hepatitis treatment.
  • Chronic hepatitis is an inflammatory disease of the liver which persists for at least 6 months and is considered to be caused by an infection by the hepatitis virus, autoimmunity, certain kinds of drugs, and the like.
  • a liver disease will take the course of an occurrence of a transitional extension, chronic change, and inverterate hepatitis, and in some cases, that the disease takes 10 or more years before healing or the disease may be migrated to cirrhosis, and a further complication of primary hepatoma may cause death in many cases.
  • the migration percentage from chronic hepatitis to cirrhosis is not constant, depending on the source, but is approximately 40%.
  • the healing percentage is much smaller, and has been estimated to be around 10%. Accordingly, about half of the cases have persistent subjective symptoms and liver function abnormalities and are difficult to cure.
  • Chronic hepatitis is classified into an active type and a nonactive type, by liver function and liver biopsis image, and the active type and nonactive type are mutually migratable to each other.
  • the therapy therefore is performed at the time when an active lesion exists and the practiced drug therapy is based on instructions on food intake and how to relax.
  • Neo Minofagen C ⁇ as liver protecting agents, interferon (IFN), arabinoside-A (Ara-A) as antiviral agents, and glucocorticoid (GC) withdrawal as the immune control therapy have been practiced, but some problems arise in the use of these prior art methods.
  • IFN interferon
  • Ara-A arabinoside-A
  • GC glucocorticoid
  • the objects of the present invention are to eliminate the above-mentioned disadvantages of the prior art and to provide a pharmaceutical preparation for chronic hepatitis treatment capable of being orally administered and having few side effects and a high efficacy.
  • a pharmaceutical preparation for chronic hepatitis treatment comprising an active vitamin D, as an active ingredient, and a carrier therefore.
  • Figure 1 shows the change of GOT when l ⁇ -hydroxy- vitamin D 3 is administered.
  • Fig. 2 shows the change of GPT when l ⁇ -hydroxy- vitamin D is administered.
  • Active vitamin D's such as la-hydroxyvitamin D, l 24(R)-dihydroxyvitamin D, l ⁇ , 25-dihydroxyvitamin D, promote an absorption of calcium in the small intestine promote bone resorption and bone formation in bones, an are well known in the art as a therapeutic agent for diseases due to various calcium metabolism abnor ⁇ malities.
  • the present inventors made an intensive investiga- tion of the effects of the active vitamin D on chronic hepatitis, and consequently, surprisingly found that th active vitamin D has the action of lowering the GOT and GPT, which are indices of liver function.
  • the active vitamin D usable in the present invention includes the active vitamin D « , the active vitamin D, , and derivatives thereof.
  • Typical examples of such compounds are l ⁇ -hydroxyvitamin D, l ⁇ , 24(R)- dihydroxyvita in D, l ⁇ , 25-dihydroxyvitamin D, l ⁇ , 24 25-trihydroxyvitamin D, 24, 24-difluoro-l f 25-dihy- droxyvita in D, 26, 26, 26, 27, 27, 27-hexafluoro-l ⁇ , 25-dihydroxyvitamin D, 25-hydroxyvitamin D.,-26, 23-lactone and l ⁇ , 25-dihydroxyvitamin D-,-26, 23-lactone.
  • l ⁇ -hydroxy ⁇ vitamin D, , l ⁇ » 24(R)-dihydroxyvitamin D, , l ⁇ j 25-dihydroxyvitamin D are preferable, and particularly l ⁇ , hydroxyvitamin D, is most preferred.
  • active ingredients can be used as oral preparation in the form of, for example, soft capsules, hard capsules, tablets, powders, granules, or syrup, or optionally can be used as parenteral preparations in th form of injections, or external preparations, with the use of appropriate vehicles including excipients according to conventional methods.
  • Examples of the vehicles usable in the present invention are vegetable oil or mineral oils, white petrolatum, branched chain fats or oils, animal fats an high molecular weight alcohols for liquid agents or external application agents.
  • vegetable oils corn oil, cotton oil, coconut oil, almond oil
  • middle chain length fatty acid triglycerides are preferred.
  • examples of the vehicles for solid agents usable are cellulose derivatives (crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, methyl cellulose), polyvinylpyrolidone, dextrin, cyclodextrin, casein, lactose, mannitol, gelatin or starch. Among them, lactose, polyvinylpyrolidone etc. are preferred.
  • the content of the active ingredient i.e., the active vitamin D in the composition
  • the content of the active ingredient is preferably (0.00004 - 0.2) x 10 -4% by
  • the dose of the active ingredient is preferably about 0.01 to 10 ⁇ g/day/person, more preferably 0.25 to
  • preparations are obtained which satisfy such conditions.
  • Example 1 Active vitamin D- , l ⁇ -Hydroxyvitamin D_, ,
  • Fig. 1 and Fig. 2 The mean GOT and GPT levels for 6 months before and after the administration are shown in Fig. 1 and Fig. 2, respectively. It is clear from Fig. 1, that the mean GOT level was reduced from 173.9 KU to 83.1 KU by the treatment. It was also confirmed that the mean GPT level was reduced from 172.4 KU to 83.2 KU. These reductions of GOT and GPT levels to 100 or less after administration, it is expected that the migration from chronic hepatitis to cirrhosis can be inhibited. Also, hypercalcemia and side effects were not observed during the test period.
  • BLP 300 ⁇ q protein/ml
  • CFA Complete Freund's Adjuvant
  • mice To DBA/2 strain male mice (7 weeks old) were intraperitoneally injected with 0.25 ml of rabbit ⁇ globulin (RGG» 4 mg/ml) emulsified with an equal volume of CFA. Five days later, 0.6 ml of the anti-BLP antibody was injected through the tail vein, and blood for GPT assay was collected from the right ventricle 18 hours after antibody injection. l ⁇ -OH-D, (0.8, 4, or 20 ng/kg/day) was orally administered once a daily for 7 days from one day before the RGG injection. The results are shown in Table 1.
  • the mean GPT level was 72.5 KU/1, which was clearly higher than that of normal mice and RGG-treated mice: mean levels 14.0 and 11.8 KU/1, respectively.
  • l ⁇ -0H-D 3 at doses of 0.8, 4 and 20 ng/kg/day, inhibited the mean GPT level by 40.3, 45.7, and 44.8%, respectively.
  • Example 3 acnes LPS-induced Hepatitis Model .
  • Balb/c mice (male, 8 weeks old) were injected with 0.1 mg of heat-killed Propionibacterium acnes (P. acnes) through the tail vein.
  • P. acnes heat-killed Propionibacterium acnes
  • 3 ⁇ q of lipopolysaccharide (LPS) derived from E. coli was injected through the same route. Blood was collected 18 hours thereafter, from the right ventricle, and the serum GPT level was measured.
  • l ⁇ -OH-D (4, 100 ng/kg/day) was orally administered for 9 days from one day before the P. acnes treatment. The results are shown in Table 2.
  • Active vitamin D, , l ⁇ -hydroxyvitamin D, was orally administered, at a dose of 1.5 ⁇ q/day for 14 months into to a patient (female, age 50) with chronic hepatitis confirmed by liver biopsy and serologic study.
  • the liver function (GOT, GPT) and the liver biopsy were evaluated.
  • the GOT and GPT levels were reduced from 130 KU and 132 KU, and from 132 KU to 30 KU, respectively. It was confirmed by a tissue observation of the liver bio ass examination that the remarkable decrease in the inflammation observed before and after the administration. The histopathological finding was not substantially different from normal tissue. No side effects such as hypercalcemia were observed during the examination.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une préparation pharmaceutique de traitement de l'hépatite chronique, contenant une vitamine D active à titre d'ingrédient actif, ainsi qu'un support prévu pour cette dernière. A titre d'exemple de vitamine D active, on peut citer des composés tels que 1 alpha-hydroxyvitamine D, 1 alpha, 24(R)-dihydroxy-vitamine D, 1 alpha, 25-dihydroxyvitamine D, 1 alpha, 24,25-trihydroxyvitamine D, 26,26,26,27,27,27-hexafluoro-1 alpha, 25-dihydroxyvitamine D, 25-hydroxyvitamine D3-26, 23-lactone, 1-alpha, 25-dihydroxyvitamine D3-26,23-lactone.The invention relates to a pharmaceutical preparation for the treatment of chronic hepatitis, containing an active vitamin D as an active ingredient, as well as to a carrier provided therefor. By way of example of active vitamin D, mention may be made of compounds such as 1 alpha-hydroxyvitamin D, 1 alpha, 24 (R) -dihydroxy-vitamin D, 1 alpha, 25-dihydroxyvitamin D, 1 alpha, 24,25 -trihydroxyvitamin D, 26,26,26,27,27,27-hexafluoro-1 alpha, 25-dihydroxyvitamin D, 25-hydroxyvitamin D3-26, 23-lactone, 1-alpha, 25-dihydroxyvitamin D3-26,23- lactone.

Description

DESCRIPTION
TITLE OF THE INVENTION
Active vitamin D for chronic hepatitis treatment
TECHNICAL FIELD The present invention relates to a pharmaceutical preparation for chronic hepatitis treatment. BACKGROUND ART
Chronic hepatitis is an inflammatory disease of the liver which persists for at least 6 months and is considered to be caused by an infection by the hepatitis virus, autoimmunity, certain kinds of drugs, and the like. Generally, it has been found that a liver disease will take the course of an occurrence of a transitional extension, chronic change, and inverterate hepatitis, and in some cases, that the disease takes 10 or more years before healing or the disease may be migrated to cirrhosis, and a further complication of primary hepatoma may cause death in many cases. The migration percentage from chronic hepatitis to cirrhosis is not constant, depending on the source, but is approximately 40%. On the other hand, the healing percentage is much smaller, and has been estimated to be around 10%. Accordingly, about half of the cases have persistent subjective symptoms and liver function abnormalities and are difficult to cure.
Chronic hepatitis is classified into an active type and a nonactive type, by liver function and liver biopsis image, and the active type and nonactive type are mutually migratable to each other. The therapy therefore is performed at the time when an active lesion exists and the practiced drug therapy is based on instructions on food intake and how to relax.
In the prior art, as a drug therapy, a therapy with the use of strong Neo Minofagen C ^ as liver protecting agents, interferon (IFN), arabinoside-A (Ara-A) as antiviral agents, and glucocorticoid (GC) withdrawal as the immune control therapy have been practiced, but some problems arise in the use of these prior art methods. Namely, in the case of the Strong Neo Minofagen C ^, since it is injected, it is not suitable for a long term therapy; in the case of IFN, fervescence, a reduction of leukocyte and platelet numbers, and other side effects occur; in the case of Ara-A, a reduction in leukocyte and platelet numbers and a peripheral nervous disorder are liable to be exhibited; and in the case of GC, since the DNAp activity is inevitably increased one week after administration, it must be carefully administered. Accordingly, there is an urgent need to develop a therapeutic composition which can be orally adminis- tered, has few side effects and has a high efficacy.
DISCLOSURE OF THE INVENTION
Accordingly, the objects of the present invention are to eliminate the above-mentioned disadvantages of the prior art and to provide a pharmaceutical preparation for chronic hepatitis treatment capable of being orally administered and having few side effects and a high efficacy.
Other objects and advantages of the present invention will be apparent from the following description.
In accordance with the present invention, there is provided a pharmaceutical preparation for chronic hepatitis treatment comprising an active vitamin D, as an active ingredient, and a carrier therefore. BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be better understood from the description set forth below with reference to the accompanying drawings; wherein;
Figure 1 shows the change of GOT when lα-hydroxy- vitamin D3 is administered; and
Fig. 2 shows the change of GPT when lα-hydroxy- vitamin D is administered. PCI7JP89/01257
- 3 -
BEST MODE OF CARRYING OUT THE INVENTION Active vitamin D's such as la-hydroxyvitamin D, l 24(R)-dihydroxyvitamin D, lα, 25-dihydroxyvitamin D, promote an absorption of calcium in the small intestine promote bone resorption and bone formation in bones, an are well known in the art as a therapeutic agent for diseases due to various calcium metabolism abnor¬ malities.
The present inventors made an intensive investiga- tion of the effects of the active vitamin D on chronic hepatitis, and consequently, surprisingly found that th active vitamin D has the action of lowering the GOT and GPT, which are indices of liver function.
The active vitamin D usable in the present invention includes the active vitamin D« , the active vitamin D, , and derivatives thereof. Typical examples of such compounds are lα-hydroxyvitamin D, lα, 24(R)- dihydroxyvita in D, lα, 25-dihydroxyvitamin D, lα, 24 25-trihydroxyvitamin D, 24, 24-difluoro-l f 25-dihy- droxyvita in D, 26, 26, 26, 27, 27, 27-hexafluoro-lα, 25-dihydroxyvitamin D, 25-hydroxyvitamin D.,-26, 23-lactone and lα, 25-dihydroxyvitamin D-,-26, 23-lactone. Among these examples, lα-hydroxy¬ vitamin D, , lα» 24(R)-dihydroxyvitamin D, , lαj 25-dihydroxyvitamin D, are preferable, and particularly lα, hydroxyvitamin D, is most preferred.
These active ingredients can be used as oral preparation in the form of, for example, soft capsules, hard capsules, tablets, powders, granules, or syrup, or optionally can be used as parenteral preparations in th form of injections, or external preparations, with the use of appropriate vehicles including excipients according to conventional methods.
Examples of the vehicles usable in the present invention are vegetable oil or mineral oils, white petrolatum, branched chain fats or oils, animal fats an high molecular weight alcohols for liquid agents or external application agents. Among these vehicles, vegetable oils (corn oil, cotton oil, coconut oil, almond oil), especially middle chain length fatty acid triglycerides are preferred. Examples of the vehicles for solid agents usable are cellulose derivatives (crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, methyl cellulose), polyvinylpyrolidone, dextrin, cyclodextrin, casein, lactose, mannitol, gelatin or starch. Among them, lactose, polyvinylpyrolidone etc. are preferred. Although there are no limitations to the content of the active ingredient, i.e., the active vitamin D in the composition, the content of the active ingredient is preferably (0.00004 - 0.2) x 10 -4% by
-4 weight, more preferably (0.001 - 0.08) x 10 % by weight in the composition.
The dose of the active ingredient is preferably about 0.01 to 10 μg/day/person, more preferably 0.25 to
4.0 μg/day/person, and the administration is preferably made 1 to 3 times/day. Preferably, preparations are obtained which satisfy such conditions.
The method of the present invention can be also used in combination with known drug therapy therapeutic agents. EXAMPLES
The present invention will now be further illus¬ trated by, but is by no means limited to, the following Examples.
Example 1 Active vitamin D- , lα-Hydroxyvitamin D_, ,
(lα-0H-D3) was orally administered to 11 patients with chronic hepatitis confirmed by liver biopsy and serologic study (9 males, 2 females, average age 51.5) at daily doses of 0.5 to 2.0 μq . Soft capsules comprising 0.5 - 2.0 μg of lα-OH-D3 and 150 mg of triglycerides of medium-chain fatty acids were used for the administration. The liver function was evaluated by serologic study (GOT, GPT) once a month for 6 months before and after the administration.
The mean GOT and GPT levels for 6 months before and after the administration are shown in Fig. 1 and Fig. 2, respectively. It is clear from Fig. 1, that the mean GOT level was reduced from 173.9 KU to 83.1 KU by the treatment. It was also confirmed that the mean GPT level was reduced from 172.4 KU to 83.2 KU. These reductions of GOT and GPT levels to 100 or less after administration, it is expected that the migration from chronic hepatitis to cirrhosis can be inhibited. Also, hypercalcemia and side effects were not observed during the test period.
Example 2; Anti-BLP Antibody induced Hepatitis Model
The experiment was performed according to the method of Nagai et al. (Japanese Journal of Inflammation ξ_, 361 (1986)). Namely, liver was removed from DBA/2 strain male mice (male, 7 weeks old), and a 50 wt% homogenate was prepared with physiological saline.
Supernatant fluid obtained by centrifugation at 4°C and 8000 rpm for 30 minutes was adjusted to pH 4.8 with acetic acid. After centrifugation, saturated ammonium sulfate was added to the supernatant and the fractions precipitated at 35 to 60% were obtained. The precipitates were dissolved in distilled water, and dialyzed against 0.005 M Tris-HCl buffer (pH 8.0). The dialyzed solution was applied to a DEAE cellulose column chromatography equilibrated with 0.005 M Tris-HCl buffer (pH 8.0), and the fractions eluted were made into basic liver protein (BLP).
One ml of BLP (300 μq protein/ml) was emulsified with an equal volume of Complete Freund's Adjuvant (CFA), the emulsified mixture was immunized to a New Zealand White rabbit (female, 2.0 to 2.5 kg) every week for 4 to 6 weeks. Ten days after the final immunization, blood was collected from the cervical aorta and serum was obtained. After inactivation of complement by heat treatment at 56°C for 30 minutes, the serum was absorbed with mouse kidney homogenate and rat erythrocytes to obtain a specific antibody to BLP. To DBA/2 strain male mice (7 weeks old) were intraperitoneally injected with 0.25 ml of rabbit Ύ globulin (RGG» 4 mg/ml) emulsified with an equal volume of CFA. Five days later, 0.6 ml of the anti-BLP antibody was injected through the tail vein, and blood for GPT assay was collected from the right ventricle 18 hours after antibody injection. lα-OH-D, (0.8, 4, or 20 ng/kg/day) was orally administered once a daily for 7 days from one day before the RGG injection. The results are shown in Table 1.
In anti-BLP antibody-treated mice, the mean GPT level was 72.5 KU/1, which was clearly higher than that of normal mice and RGG-treated mice: mean levels 14.0 and 11.8 KU/1, respectively. In contrast, lα-0H-D3 , at doses of 0.8, 4 and 20 ng/kg/day, inhibited the mean GPT level by 40.3, 45.7, and 44.8%, respectively.
Example 3: . acnes LPS-induced Hepatitis Model . Balb/c mice, (male, 8 weeks old) were injected with 0.1 mg of heat-killed Propionibacterium acnes (P. acnes) through the tail vein. Seven days later, 3 μq of lipopolysaccharide (LPS) derived from E. coli was injected through the same route. Blood was collected 18 hours thereafter, from the right ventricle, and the serum GPT level was measured. lα-OH-D, (4, 100 ng/kg/day) was orally administered for 9 days from one day before the P. acnes treatment. The results are shown in Table 2.
In P. acnes and LPS-treated a hepatitic mice, the mean GPT level was increased to 680 KU/1. In contrast, lα-OH-D3 , at doses of, 4, and 100 ng/kg/day inhibited the mean GPT level by 27.2% and 52.8%, respectively. Example 4
Active vitamin D, , lα-hydroxyvitamin D, , was orally administered, at a dose of 1.5 μq/day for 14 months into to a patient (female, age 50) with chronic hepatitis confirmed by liver biopsy and serologic study. The liver function (GOT, GPT) and the liver biopsy were evaluated.
The GOT and GPT levels were reduced from 130 KU and 132 KU, and from 132 KU to 30 KU, respectively. It was confirmed by a tissue observation of the liver bio ass examination that the remarkable decrease in the inflammation observed before and after the administration. The histopathological finding was not substantially different from normal tissue. No side effects such as hypercalcemia were observed during the examination.

Claims

1. A pharmaceutical preparation for chronic hepatitis treatment comprising an active vitamin D, as an active ingredient, and a carrier therefore.
2. A pharmaceutical preparation for chronic hepatitis treatment as claimed in claim 1, wherein the active vitamin D is at least one compound selected from the group consisting of lα-hydroxyvitamin D, l f 24(R)-dihydroxyvitamin D, lα, 25-dihydroxyvitamin D, lα, 24, 25-trihydroxyvitamin D, 24, 24-difluoro-lαj 25-dihydroxyvitamin D, 26, 26, 26, 27, 27, 27,
27-hexafluoro-lα, 25-dihydroxyvitamin D, 25-hydroxy- vitamin D,-26, 23-lactone, lα, 25-dihydroxyvitamin D3-26, 23-lactone.
3. A pharmaceutical preparation for chronic hepatitis treatment as claimed in claim 1, wherein the content of the active ingredient is (0.00004 - 0.2) x 10 -4% by weight of the composition.
EP90900979A 1988-12-14 1989-12-14 Active vitamin d for chronic hepatitis treatment Withdrawn EP0409994A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP313753/88 1988-12-14
JP31375388 1988-12-14

Publications (1)

Publication Number Publication Date
EP0409994A1 true EP0409994A1 (en) 1991-01-30

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Country Status (5)

Country Link
EP (1) EP0409994A1 (en)
KR (1) KR910700053A (en)
AU (1) AU4742890A (en)
CA (1) CA2005227A1 (en)
WO (1) WO1990006754A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997032998A2 (en) * 1996-03-08 1997-09-12 Isis Innovation Limited Materials and methods relating to the identification of a polymorphism associated with disease susceptibility
BR112013011259B1 (en) 2010-12-06 2020-03-03 Dsm Ip Assets Bv Use of 25-hydroxyvitamin D3 to manufacture a pharmaceutical, food, or nutraceutical product to maintain healthy levels of eotaxin

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2389377A1 (en) * 1977-05-06 1978-12-01 Brohult Johan Antiinflammatory, antirheumatic medicament - comprises 1 alpha-hydroxy-cholecalciferol
JPS5626820A (en) * 1979-08-10 1981-03-16 Chugai Pharmaceut Co Ltd Immunosuppressing agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9006754A1 *

Also Published As

Publication number Publication date
CA2005227A1 (en) 1990-06-14
WO1990006754A1 (en) 1990-06-28
KR910700053A (en) 1991-03-13
AU4742890A (en) 1990-07-10

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