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EP0550529A1 - Pharmaceutical composition comprising cd4 and a polyanionic anti-hiv agent and use thereof - Google Patents

Pharmaceutical composition comprising cd4 and a polyanionic anti-hiv agent and use thereof

Info

Publication number
EP0550529A1
EP0550529A1 EP91916829A EP91916829A EP0550529A1 EP 0550529 A1 EP0550529 A1 EP 0550529A1 EP 91916829 A EP91916829 A EP 91916829A EP 91916829 A EP91916829 A EP 91916829A EP 0550529 A1 EP0550529 A1 EP 0550529A1
Authority
EP
European Patent Office
Prior art keywords
agent
hiv
polyanionic
virus
effective dose
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Withdrawn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
EP91916829A
Other languages
German (de)
French (fr)
Inventor
Donald Selwyn 7 Mynden Close Davies
Jonathan Norden Weber
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.)
Innovata Ltd
Original Assignee
ML Laboratories PLC
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 ML Laboratories PLC filed Critical ML Laboratories PLC
Publication of EP0550529A1 publication Critical patent/EP0550529A1/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Withdrawn legal-status Critical Current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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/12—Antivirals

Definitions

  • This invention relates to pharmaceutically active compositi and to their use as agents against human immunodeficiency vi and related viruses.
  • the HIV infection cycle includes a number of steps, each of th steps being a possible target for the use of chemotherapy hinder the infection.
  • the first step in the infection cycle the attachment of the HIV virus to the host cell.
  • the m receptor for the virus is believed to be the cell surf glycoprotein, designated CD4, which is present in some lymphocytes and in some macrophages. Much attention therefore been given to identifying agents which are capable blocking attachment of the virus to CD4.
  • statin CD4 made by genetic engineering, can block attachment of H virus to cellular CD4, thereby inhibiting HIV infection in vitr
  • CD4-li materials capable of binding to gpl20, such as CD4-Ig immunoadhesins, CD4 V1-V2 domains, and CD4-derived peptides, ha also been proposed as anti-HIV agents.
  • CD4-Ig immunoadhesins CD4 V1-V2 domains
  • CD4-derived peptides ha also been proposed as anti-HIV agents.
  • the performan of CD4 and CD4-like materials in preventing the HIV virus fr binding to cells has until now been disappointing, a much high concentration of the agent being necessary than had been hoped.
  • anti-HIV agents which block attachment of the virus cells are a number of polyanionic compounds which include Eva Blue, aurintricarboxylic acid (ATA), suramin, and certai sulphated polysaccharides. It might have been thought that i CD4 and such polyanionic anti-HIV agents were use simultaneously, the total anti-HIV activity would at best be th sum of their separate activities.
  • CD4 which is used here an below, except where otherwise indicated, to include both CD4 an CD4-like materials
  • a polyanionic anti-HIV agent such as a sulphated polysaccharide
  • the invention provides an agent against HIV an related viruses, in dosage unit form, comprising CD4 or a CD4 like material and a polyanionic anti-HIV agent the content of CD and CD4-like material in the agent being less than the anti virally effective dose of the CD4 or CD4-like material alone.
  • the agent according to the invention may contain substantiall less CD4 than the anti-virally effective dosage of CD4 alo i.e. in the absence of a polyanionic anti-HIV agent.
  • reduction in the amount of CD4 required to achieve the same an viral effect as for CD4 alone may be such that less than o tenth (or, in favourable cases, less than one-hundredth) of amount of CD4 is needed.
  • the invention offers possibility of using CD4 as a component of an anti-HIV agent i reduced and therefore safer and more economical amount than previously been feasible.
  • the agent according to the invention may also contain less t the normally effective dose of the polyanionic compound. This advantageous because many of the known polyanionic anti- agents are significantly toxic. For example, sulphat polysaccharides have anti-coagulant activity. When t polyanionic anti-HIV agent is a sulphated polysaccharide, it m be present in the compositions of the invention in an amou which is less than that which would be required in an anti-H agent containing only the sulphated polysaccharide.
  • compositions of the invention which conta sulphated polysaccharides may have a lower level of ant coagulant activity attributable to the sulphated polysacchari content than those previously known.
  • the polyanionic anti-HIV agents used in the present invention a preferably sulphated polysaccharides. They include, for exampl dextran sulphate, pentosan polysulphate, fucoidan, and dextr sulphate. Other sulphated polysaccharides having anti-H activity (see, for example, EP specifications No's 240,098 a 293,826) may also be used.
  • the sulphat polysaccharide contains at least one sulphate group p saccharide unit.
  • the anti-HIV agent of the invention may administered enterally (including orally) or parenteral (including intravenously).
  • administration via t peritoneum may be more effective in that it results in entry at least some of the anti-HIV agent directly into the lymphat system, within which system viral replication may be extensive.
  • the invention also provides the use of the agent described abo against HIV-1 and relates viruses, the agent preferably bei administered peritoneally.
  • the invention provides a pharmaceutical compositi containing the anti-HIV agent of the invention together with inert carrier or diluent and the agent of the invention for u in the manufacture of a pharmaceutical composition against HIV and related viruses.
  • the invention additionally provides a method of treatment of human or animal subject carrying the HIV-1 virus or a rela virus, comprising administering to the subject a pharmaceutica effective amount of the agent of the invention.
  • the CD4 or CD4-like material and the polyanionic anti-HIV ag may be administered to a subject one after the other, in order although preferably with the CD4 or CD4-like mater being administered before the polyanionic agent, when u against HIV-1 or a related virus.
  • the invention thus provides CD4 or a CD4-like material, of amount less than its usual anti-virally effective dose, and polyanionic anti-HIV agent, for use in a method of treatment of human or animal subject carrying the HIV-1 virus or a relat virus in whic the CD4 or CD4-like material are administered the subject one after the other.
  • T dextrin sulphate was produced by sulphation of a dextrin weight average molecular weight of about 20,000 daltons, using sulphur trioxide/trimethylamine complex, the degree substitution being approximately one sulphate group per gluco unit.
  • the srCD4 was produced in a baculo virus system and w purchased from American Biotechnology Inc.
  • Example 1
  • T srCD4/HIV-l was then added to the dextrin sulphate pre-treat M8166 cells, and the plates read at 48 - 72 hours for t presence of syncytia, shown in the table below by +.
  • srCD4 inhibited HIV infection of M8166 cells at 6 ug/ml (final concentration).
  • dextrin sulphate inhibited HIV-1 infecti of M8166 cells at 5-10 ug/ml.
  • 2 - 5.0 ug/ml of dextrin sulphate inhibited HIV-1 infection in t presence of srCD4 at a concentration of 0.05 - 0.09 ug/ml.
  • Th represents a 10 ⁇ reduction in the quantity of srCD4 required prevent HIV-1 infection, and shows that the effect of the t drugs together is synergistic rather than simply additive.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Cell Biology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention se rapporte à un agent anti-VIH et virus apparentés, sous forme pharmaceutique unitaire, comprenant la glycoprotéine de surface cellulaire CD4 ou une substance similaire à CD4 et un agent polyanionique anti-VIH, la quantité de CD4 ou de substance similaire à CD4 dans l'agent étant inférieure à la dose anti-virale efficace de CD4 ou de substance similaire seule. On a découvert que, quand on utilise CD4 ou la substance similaire avec un agent polyanionique anti-VIH, la combinaison est plus efficace contre l'infection par VIH que ce ne serait le cas si l'effet anti-viral était uniquement additif.The invention relates to an anti-HIV agent and related viruses, in unitary pharmaceutical form, comprising the cell surface glycoprotein CD4 or a substance similar to CD4 and a polyanionic anti-HIV agent, the amount of CD4 or similar substance to CD4 in the agent being less than the effective anti-viral dose of CD4 or similar substance alone. It has been found that when CD4 or the like is used with a polyanionic anti-HIV agent, the combination is more effective against HIV infection than it would be if the anti-viral effect was only additive.

Description

PHARMACEUTICALCOMPOSITIONCOMPRISINGCD4ANDAPOLYANIONICANTI- HIVAGENTAND USETHEREOF
This invention relates to pharmaceutically active compositi and to their use as agents against human immunodeficiency vi and related viruses.
The HIV infection cycle includes a number of steps, each of th steps being a possible target for the use of chemotherapy hinder the infection. The first step in the infection cycle the attachment of the HIV virus to the host cell. The m receptor for the virus is believed to be the cell surf glycoprotein, designated CD4, which is present in some lymphocytes and in some macrophages. Much attention therefore been given to identifying agents which are capable blocking attachment of the virus to CD4.
It is believed that the HIV virus attaches itself to CD4 by mea of interaction between CD4 and the surface glycoprotein, gpl2 of the virus. It has been found that soluble recombinant C
(srCD4), made by genetic engineering, can block attachment of H virus to cellular CD4, thereby inhibiting HIV infection in vitr
Therefore, it has appeared that HIV infection might preventable by administration of srCD4. Other CD4-li materials, capable of binding to gpl20, such as CD4-Ig immunoadhesins, CD4 V1-V2 domains, and CD4-derived peptides, ha also been proposed as anti-HIV agents. However, the performan of CD4 and CD4-like materials in preventing the HIV virus fr binding to cells has until now been disappointing, a much high concentration of the agent being necessary than had been hoped.
Other anti-HIV agents which block attachment of the virus cells are a number of polyanionic compounds which include Eva Blue, aurintricarboxylic acid (ATA), suramin, and certai sulphated polysaccharides. It might have been thought that i CD4 and such polyanionic anti-HIV agents were use simultaneously, the total anti-HIV activity would at best be th sum of their separate activities.
However, we have now found that when CD4 (which is used here an below, except where otherwise indicated, to include both CD4 an CD4-like materials) and a polyanionic anti-HIV agent, such a sulphated polysaccharide, are used together, they are much mor effective against HIV infection than would be the case if th anti-viral effect was simply additive.
Accordingly, the invention provides an agent against HIV an related viruses, in dosage unit form, comprising CD4 or a CD4 like material and a polyanionic anti-HIV agent the content of CD and CD4-like material in the agent being less than the anti virally effective dose of the CD4 or CD4-like material alone.
The agent according to the invention may contain substantiall less CD4 than the anti-virally effective dosage of CD4 alo i.e. in the absence of a polyanionic anti-HIV agent. reduction in the amount of CD4 required to achieve the same an viral effect as for CD4 alone may be such that less than o tenth (or, in favourable cases, less than one-hundredth) of amount of CD4 is needed. Accordingly, the invention offers possibility of using CD4 as a component of an anti-HIV agent i reduced and therefore safer and more economical amount than previously been feasible.
The agent according to the invention may also contain less t the normally effective dose of the polyanionic compound. This advantageous because many of the known polyanionic anti- agents are significantly toxic. For example, sulphat polysaccharides have anti-coagulant activity. When t polyanionic anti-HIV agent is a sulphated polysaccharide, it m be present in the compositions of the invention in an amou which is less than that which would be required in an anti-H agent containing only the sulphated polysaccharide.
Consequently, the compositions of the invention which conta sulphated polysaccharides may have a lower level of ant coagulant activity attributable to the sulphated polysacchari content than those previously known.
The polyanionic anti-HIV agents used in the present invention a preferably sulphated polysaccharides. They include, for exampl dextran sulphate, pentosan polysulphate, fucoidan, and dextr sulphate. Other sulphated polysaccharides having anti-H activity (see, for example, EP specifications No's 240,098 a 293,826) may also be used. Preferably, the sulphat polysaccharide contains at least one sulphate group p saccharide unit.
In therapeutic use, the anti-HIV agent of the invention may administered enterally (including orally) or parenteral (including intravenously). However, administration via t peritoneum may be more effective in that it results in entry at least some of the anti-HIV agent directly into the lymphat system, within which system viral replication may be extensive.
The invention also provides the use of the agent described abo against HIV-1 and relates viruses, the agent preferably bei administered peritoneally.
Further, the invention provides a pharmaceutical compositi containing the anti-HIV agent of the invention together with inert carrier or diluent and the agent of the invention for u in the manufacture of a pharmaceutical composition against HIV and related viruses.
The invention additionally provides a method of treatment of human or animal subject carrying the HIV-1 virus or a rela virus, comprising administering to the subject a pharmaceutica effective amount of the agent of the invention.
The CD4 or CD4-like material and the polyanionic anti-HIV ag may be administered to a subject one after the other, in order although preferably with the CD4 or CD4-like mater being administered before the polyanionic agent, when u against HIV-1 or a related virus.
The invention thus provides CD4 or a CD4-like material, of amount less than its usual anti-virally effective dose, and polyanionic anti-HIV agent, for use in a method of treatment of human or animal subject carrying the HIV-1 virus or a relat virus in whic the CD4 or CD4-like material are administered the subject one after the other.
The following example illustrates the synergistic action dextrin sulphate with soluble recombinant CD4 (srCD4). T dextrin sulphate was produced by sulphation of a dextrin weight average molecular weight of about 20,000 daltons, using sulphur trioxide/trimethylamine complex, the degree substitution being approximately one sulphate group per gluco unit. The srCD4 was produced in a baculo virus system and w purchased from American Biotechnology Inc. Example 1
In a duplicated experiment, 2-fold dilutions of solub recombinant CD4, to yield final concentrations of 6 ug/ml down 0.02 ug/ml, were incubated with 2.5 x 103 TCID (tissue cultu infection dose) of HIV-1 virus supernatant (HTLV-IIIb strai Gallo, 1984) at 37°C for 1 hour. 2-fold dilutions of dextr sulphate to yield final concentrations from 10 ug/ml down 0.625 ug/ml were then added to the T-cell line, M8166, at density of 2.5 x 105/ml and incubated at 37°C for 1 hour. T srCD4/HIV-l was then added to the dextrin sulphate pre-treat M8166 cells, and the plates read at 48 - 72 hours for t presence of syncytia, shown in the table below by +.
In the absence of dextrin sulphate, srCD4 inhibited HIV infection of M8166 cells at 6 ug/ml (final concentration). the absence of srCD4, dextrin sulphate inhibited HIV-1 infecti of M8166 cells at 5-10 ug/ml. When both drugs were present, 2 - 5.0 ug/ml of dextrin sulphate inhibited HIV-1 infection in t presence of srCD4 at a concentration of 0.05 - 0.09 ug/ml. Th represents a 10^ reduction in the quantity of srCD4 required prevent HIV-1 infection, and shows that the effect of the t drugs together is synergistic rather than simply additive.
FIRST EXPERIMENT
Dextrin srCD4 (ug/ml)
Sulphate
(ug/ml)
1.5 0.75 0.375 0.18 0.09 0.05 0.
5
2.5
1.25 + +
0.625 + +
0
SECOND EXPERIMENT
Dextrin srCD4 (ug/ml)
Sulphate
(ug/ml)
1.5 0.75 0.375 0.18 0.09 0.05 0.
10
+
+ + +
+ + + + + + + + + + + + + + + + + + + + + + + + + + METHOD srCD4 diluted into 96 well tray. Add 2.5 x 103 TCID Illb. Incubate at 37oC for 1 hour.
B Dextrin sulphate diluted into another well tray. Add M8166 (2.5 x 105/ml). Incubate at 37°C for 1 hour.
Then add A to B.
Read at 2 - 3 days when positive controls show >95% syncytia.

Claims

1. An agent against HIV and related viruses, in dosage u form, comprising CD4 or a CD4-like material and polyanionic anti-HIV agent, the content of CD4 or CD4-l material in the agent being less than the anti-vira effective dose of the CD4 or CD4-like material alone.
2. The agent of Claim 1 wherein the content of CD4 or CD4-l material is less than one-tenth of the anti-vira effective dose of the Cd4 or CD4-like material alone.
3. The agent of Claim 1 wherein the content of CD4 or CD4-li material is less than one-hundredth of the anti-viral effective dose of the Cd4 or CD4-like material alone.
4. The agent of any of Claims 1 to 3 wherein the content said polyanionic anti-HIV agent is less than the ant virally effective dose of the polyanionic anti-HIV age alone.
5. The agent of any of Claims 1 to 4 wherein said polyanion anti-HIV agent is a sulphated polysaccharide.
6. The agent of Claim 5 wherein the sulphated polysaccharide dextrin sulphate.
7. The agent of Claim 5 or 6 wherein said sulphat polysaccharide contains at least one sulphate group p saccharide unit.
8. The use of an agent according to any preceding claim again HIV-1 and related viruses.
9. The use of an agent, as claimed in Claim 8, wherein t agent is administered peritoneally.
10. The agent of any of Claims 1 to 7, adapted f intraperitoneal administration.
11. The agent of any of Claims 1 to 7, for use in t manufacture of a pharmaceutical composition against HIV and related viruses.
12. A pharmaceutical composition containing the agent of any Claims 1 to 7 and an inert carrier or diluent.
13. A method of treatment of a human or animal subject carryi the HIV-1 virus or a related virus, comprising administeri to the subject a pharmaceutically effective amount of t agent of any of Claims 1 to 7.
14. CD4 or CD4-like material, of an amount less than its us anti-virally effective dose, and a polyanionic anti- agent, for use in a method of treatment of a human or ani subject carrying the HIV-1 virus or a related virus in wh the CD4 or CD4-like material and the polyanionic agent administered to the subject one after the other, in order.
15. A method of treatment of a human or animal subject carryi the HIV-1 virus or a related virus, comprising administeri to the subject, one after the other but in any order, CD4 a CD4-like material, of an amount less than its usual ant virally effective dose, and a polyanionic anti-HIV agent.
16. A method according to Claim 15, wherein the CD4 or CD4-li material is administered before the polyanionic anti-H agent.
EP91916829A 1990-09-25 1991-09-23 Pharmaceutical composition comprising cd4 and a polyanionic anti-hiv agent and use thereof Withdrawn EP0550529A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9020872 1990-09-25
GB909020872A GB9020872D0 (en) 1990-09-25 1990-09-25 Pharmaceutical compositions and use thereof

Publications (1)

Publication Number Publication Date
EP0550529A1 true EP0550529A1 (en) 1993-07-14

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EP91916829A Withdrawn EP0550529A1 (en) 1990-09-25 1991-09-23 Pharmaceutical composition comprising cd4 and a polyanionic anti-hiv agent and use thereof

Country Status (10)

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EP (1) EP0550529A1 (en)
JP (1) JPH06502846A (en)
AU (1) AU653962B2 (en)
CA (1) CA2092093A1 (en)
GB (1) GB9020872D0 (en)
IE (1) IE913341A1 (en)
NZ (1) NZ239909A (en)
PT (1) PT99058B (en)
WO (1) WO1992004909A1 (en)
ZA (1) ZA917596B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5272261A (en) * 1989-01-11 1993-12-21 Merrell Dow Pharmaceuticals Inc. Preparation of sulfated polysaccharide fractions
GB9209874D0 (en) * 1992-05-07 1992-06-24 Ml Lab Plc Pharmaceutical compositions
FR2838649B1 (en) * 2002-04-19 2006-01-13 Commissariat Energie Atomique ANTI-HIV COMPOSITION, METHOD OF MANUFACTURE AND MEDICINAL PRODUCT

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0293826A3 (en) * 1987-06-02 1989-05-10 Stichting REGA V.Z.W. Therapeutic and prophylactic application of sulfated polysaccharides against aids
DE3808353A1 (en) * 1988-03-12 1989-09-21 Basf Ag COMBINATIONS OF POLYSULFATED HEPARINES IN THE FIGHT AGAINST RETROVIRUS INFECTIONS
EP0378643A4 (en) * 1988-06-10 1990-12-27 Biogen, Inc. Combinations of soluble t4 proteins and anti-retroviral agents and methods for treating or preventing aids, arc and hiv infection
DE68924774T2 (en) * 1988-07-07 1996-05-02 Univ Pennsylvania MODULATION OF VIRUS-HOST CELL INTERACTIONS USING CYCLIC OLIGOSACCHARIDES.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9204909A1 *

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Publication number Publication date
GB9020872D0 (en) 1990-11-07
PT99058B (en) 1999-02-26
IE913341A1 (en) 1992-02-25
CA2092093A1 (en) 1992-03-26
AU8612791A (en) 1992-04-15
WO1992004909A1 (en) 1992-04-02
ZA917596B (en) 1992-05-27
PT99058A (en) 1992-08-31
AU653962B2 (en) 1994-10-20
JPH06502846A (en) 1994-03-31
NZ239909A (en) 1993-02-25

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