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Title:
PHARMACEUTICAL COMPOSITIONS AND THEIR USES FOR TREATMENT OF DEMYELINATING DISORDERS
Document Type and Number:
WIPO Patent Application WO/2000/001376
Kind Code:
A2
Abstract:
New therapies can be devised based upon a demonstration of the role of glutamate in the pathogenesis of demyelinating disorders. Inhibitors of the interaction of glutamate with the AMPA and/or kainate receptor complex are likely to be useful in treating demyelinating disorders and can be formulated as pharmaceutical compositions.

Inventors:
TURSKI LECHOSLAW (GB)
SMITH TERENCE (GB)
Application Number:
PCT/GB1999/002112
Publication Date:
January 13, 2000
Filing Date:
July 02, 1999
Export Citation:
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Assignee:
EISAI CO LTD (JP)
TURSKI LECHOSLAW (GB)
SMITH TERENCE (GB)
International Classes:
C07D243/02; A61K31/00; A61K31/225; A61K31/35; A61K31/40; A61K31/4245; A61K31/437; A61K31/47; A61K31/4725; A61K31/473; A61K31/4745; A61K31/498; A61K31/4985; A61K31/5025; A61K31/513; A61K31/517; A61K31/549; A61K31/551; A61K31/662; A61K31/675; A61K38/00; A61K38/17; A61K45/06; A61P25/00; A61P25/02; A61P25/28; C07D207/44; C07D215/22; C07D217/26; C07D239/91; C07D239/92; C07D241/38; C07D241/44; C07D285/24; C07D401/04; C07D401/06; C07D403/04; C07D403/06; C07D471/04; C07D487/04; C07D487/12; C07D491/056; C07D498/04; C07D513/04; C07D517/04; (IPC1-7): A61K31/00
Foreign References:
DE4239816A11994-06-01
US5750525A1998-05-12
US5597809A1997-01-28
EP0492485A11992-07-01
Other References:
ROSENBERG: "2,3 dihydroxy 6 nitro 7 sulfamoyl benzo quinoxaline reduces glia los..." JOURNAL OF NEUROSCIENCE, vol. 19, no. 1, 1999, XP000874924
MCDONALD J.W. ET AL: "Multiple classes of the oligodendrocyte lineage are highly vulnerable to excitotoxicity." NEUROREPORT, (24 AUG 1998) 9/12 (2757-2762)., XP000874902
MCDONALD, J. W. ET AL: "AMPA / kainate receptor-induced excitotoxicity mediates sublethal myelin injury and death of oligodendrocytes from spinal cord." SOCIETY FOR NEUROSCIENCE ABSTRACTS, (1998) VOL. 24, NO. 1-2, PP. 465. MEETING INFO.: 28TH ANNUAL MEETING OF THE SOCIETY FOR NEUROSCIENCE, PART LOS ANGELES, CALIFORNIA, USA NOVEMBER 7-12, 1998 SOCIETY FOR NEUROSCIENCE., XP000874858
MATUTE: "characteristics of acute and chronic kainate excitotoxicity..." PROC. NATL. ACAD. SCI. USA, vol. 55, 1998, pages 10229-10234, XP000867876
KIM, W.-G. ET AL: "AMPA/kainate receptor antagonists reduce lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-induced neurotoxicity in mixed cortica neuronal/glial cell cultures." SOCIETY FOR NEUROSCIENCE ABSTRACTS, (1998) VOL. 24, NO. 1-2, PP. 1857. MEETING INFO.: 28TH ANNUAL MEETING OF THE SOCIETY FOR NEUROSCIENCE, PART LOS ANGELES, CALIFORNIA, USA NOVEMBER 7-12, 1998 SOCIETY FOR NEUROSCIENCE., XP000884646
MCDONALD J W ET AL: "Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity." NATURE MEDICINE, (1998 MAR) 4 (3) 291-7., XP000867881
MATUTE: "glutamate receptor-mediated toxicity..." PROC. NATL. ACAD. SCI. USA, vol. 94, 1997, pages 8830-8835, XP002130788
DUSART I ET AL: "Demyelination, and remyelination by Schwann cells and oligodendrocytes after kainate-induced neuronal depletion in the central nervous system." NEUROSCIENCE, (1992 NOV) 51 (1) 137-48., XP000874928
HEWETT S J ET AL: "Potentiation of oxygen-glucose deprivation-induced neuronal death after induction of iNOS." STROKE, (1996 SEP) 27 (9) 1586-91., XP000884364
MILLER L G ET AL: "Interleukin-1 modulates GABAergic and glutamatergic function in brain." ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, (1994 OCT 31) 739 292-8., XP000884366
"Merck Manual" 1992 XP002130789 16 page 1507, paragraph 1 - line 55; figure 1C; tables 3,9 page 1316, paragraph 2 - paragraph 3; figure 1C; tables 3,9
See also references of EP 1100504A2
Attorney, Agent or Firm:
White, Martin Paul (Kilburn & Strode 20 Red Lion Street London WC1R 4PJ, GB)
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Claims:
CLAIMS
1. The use of an inhibitor of the interaction of glutamate with the AMPA receptor complex and of the interaction of glutamate with the kainate receptor complex in the manufacture of a medicament for treating a demyelinating disorder.
2. The use of an inhibitor of the interaction of glutamate with the AMPA receptor complex in the manufacture of a medicament for treating a demyelinating disorder.
3. The use of an inhibitor of the interaction of glutamate with the kainate receptor complex in the manufacture of a medicament for treating a demyelinating disorder.
4. The use according to any preceding claim, wherein the demyelinating disorder is acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, MarchifavaBignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV or HTLVmyelopathy, progressive multifocal leucoencephalopathy, or a secondary demyelinating disorder.
5. The use according to any of claims 1 to 3, wherein the secondary demyelinating disorder is CNS lupus erythematodes, polyarteriitis nodosa, Sjogren syndrome, sarcoidosis or isolated cerebral vasulitis.
6. The use according to any of claims 1 to 5, wherein the inhibitor is an antagonist of the binding of glutamate to the AMPA receptor.
7. The use according to any of claims 1 to 5, wherein the inhibitor is an antagonist of the binding of glutamate to the kainate receptor.
8. The use according to any preceding claim, wherein the inhibitor is an L glutamate derivative, an aamino3hydroxy5methyl4isoxazolepropionate drivative, arylthioxaline (42), acid amide (59), hydrazone (48), quinoline (51), <BR> <BR> <BR> quinolinone (70, 78), quinoxaline (8,9, 13,14, 15,17, 20,47, 50,52, 53,54, 55, 56), <BR> <BR> <BR> <BR> <BR> quinoxalinedione (7,11, 23,43, 57,58, 60,61, 74,77, 81), triazoloquinoxalinedione (3,4, 5), pyrrolylquinoxalindione (6), quinazolinone (22), quinazolinedione (35), quinoxalinone <BR> <BR> <BR> (29), phenylpyridazinoindoledione (41), indenopyrazinone (24,32, 63,65, 66,67, 68), imidazoloquinoxalinone (12), indolopyrazinone (64), imidazopyrazinone <BR> <BR> <BR> (31,33, 34,37, 44., 62), triazolopyrazinone (30), benzothiadiazine (16, 36), 4<BR> <BR> <BR> <BR> hydroxypyrrolone, pyrrolopyridazinone (40), phthalazine (25), quinolone (18, 19), aminoalkanoic acid (1), isatine (72), phenylazolophthalazine, amino or desamino <BR> <BR> <BR> 2, 3benzodiazepine (10,26, 27,28, 38,49, 79), 2,3benzodiazepin4one (21), imidazobenzodiazepine (71), pcarboline3carboxylic acid, alkoxyphenyl benzodiazepine, isoquinolinylcarboxylic acid derivatives (75), acetylaminophenyl dihydromethyldioxolobenzodiazepine, pyrimidinone (46), oxadiazol (80), <BR> <BR> <BR> isatinoxime, decahydroisoquinoline (69,73, 76), piperazine derivative (2), tetramic acid derivatives (39), or a sulphamate. (The reference numbers used above correspond with the numbers used in the list of antagonists provided in the description.) 9.
9. The use according to any of claims 1 to 7, wherein the inhibitor is Lglutamic acid diethylester, 2,3dihydroxy6nitro7sulfamoylbenzo (F) quinoxaline (NBQX), <BR> <BR> <BR> 6,7dinitroquinoxaline2, 3dione (DNQX), 6nitro7cyanoquinoxaline2,3dione<BR> <BR> <BR> <BR> (CNQX), 6 (1imidazolyl) 7nitroquinoxaline2,3 (1H, 4H) dione (YM90K), (3RS, 4aRS, 6RS, 8aRS) 6 (2 (lHtetrazole5yl) ethyl) decahydroisoquinoline3 carboxylic acid (LY293558), 9methylamino6nitrohexahydrobenzo(F) quinoxalinedione (PNQX), 8methyl5 (4 (N, Ndimethylsulphamoyl) phenyl) 6,7, 8,9 tetrahydrolHpyrrolo [3, 2h] isoquinoline2,3dione3O(3hydroxybutyric acid2<BR> <BR> <BR> <BR> yl) oxime (NS 1209), 6,7dichloro2 (lH) quinolinone3phosphonate (S 176252),<BR> <BR> <BR> <BR> and [1, 2,3, 4tetrahydro7morpholinyl2,3dioxo6 (trifluoromethyl) quinoxalin1 <BR> <BR> <BR> <BR> <BR> yl] methylphosphonate (ZK200775), 1 (4aminophenyl) 4methyl7,8methylene dioxy5H2, 3benzodiazepine (GYKI52466), () 1 (4aminophenyl) 4methyl7,8<BR> <BR> <BR> <BR> <BR> <BR> methylenedioxy4, 5dihydro3methylcarbamoyl2, 3benzodiazepine (GYKI53773),<BR> <BR> <BR> <BR> <BR> <BR> <BR> topiramate, 3 (2chlorophenyl) 2 [2 [6 [ (diethylamino) methyl] 2pyridinyl] ethenyl] <BR> <BR> <BR> <BR> <BR> <BR> <BR> 6fluoro4 (3H) quinazolinone (CP465022) and 5 (2 [N, Ndimethylamino] oxy<BR> <BR> <BR> <BR> <BR> <BR> phenyl) 3phenyl1, 2,4oxadiazol (BIIR561).
10. The use according to any of claims 1 to 5, wherein the inhibitor is an AMPA receptor channel blocker.
11. The use according to any of claims 1 to 5, wherein the inhibitor is a kainate receptor channel blocker.
12. The use according to claim 10, wherein the AMPA receptor channel blocker is fluorowillardiine or Joro spider toxin.
13. The use according to claim 11, wherein the kainate receptor channel blocker is fluorowillardiine or Joro spider toxin.
14. The use according to any preceding claim wherein the inhibitor is combined with one or more of : an immunosuppresive agent (e. g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone), an interferon (IFN; IFNbetala e. g. Rebif and Avonex; IFNbetalb e. g. Betaseron and Betaferon; IFNalpha2a e. g. Alphaferone; IFNalpha2b e. g. Viraferon), a phosphodiesterase type IV inhibitor, a humanised monoclonal antibody against a leukocyte adhesion molecule (e. g. Antegran), a synthetic polypeptide (e. g. glatiramer acetate, copolymer1), a tissue matrix metalloproteinase (MMP) inhibitor (e. g. hydroxamic acidbased inhibitors of MMPs) , or a tumour necrosis factor (TNF) inhibitor (e. g. Thalidomide or TNFreceptor immunoglobulin fusion protein).
15. A pharmaceutical composition comprising an inhibitor as described in any of claims 1 to 14 and a pharmaceutically acceptable carrier.
16. A combined preparation of an inhibitor as decribed in any claims 1 to 14 and one or more of : an immunosuppresive agent (e. g. corticotrophin, a glucocorticoid, cyclophosphamide, cyclosporine, azothioprine or mitozantrone), an interferon (IFN ; IFNbetala e. g. Rebif and Avonex; IFNbetalb e. g. Betaseron and Betaferon; IFN alpha2a e. g. Alphaferone; IFNalpha2b e. g. Viraferon), a phosphodiesterase type IV inhibitor, a humanised monoclonal antibody against a leukocyte adhesion molecule (e. g. Antegran), a synthetic polypeptide (e. g. glatiramer acetate, copolymer1) a tissue matrix metalloproteinase (MMP) inhibitor (e. g. hydroxamic acidbased inhibitors of MMPs) or a tumour necrosis factor (TNF) inhibitor (e. g. Thalidomide or TNFreceptor immunoglobulin fusion protein) for simultaneous, separate or sequential use in the treatment of a demyelinating disorder.
17. The invention substantially as hereinbefore described.
Description:
INTERNATIONAL SEARCH REPORT IntemationafApplicationNo PCT/GB99/02112 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT _ _ _ Categary ° C'dationofdocument,withindication.where eppropriaEa, of tha relevant peasages Relevant to oleim No. X,PMCDONALDJ.W.ETAL: Multiple classes of1-11,14, theoligodendrocytelineagearehighly15,17 vulnerabletoexcitotoxicity." NEUROREPORT,(24AUG1998)9/12 (2757-2762).,XPO00874902 seepage2761,column2,paragraph1- paragraph2 seepage2762,column2,paragraph1- paragraph2 X,PMCDONALD,J.W.ETAL:"AMPA/kainate 1-11, 14, receptor-inducedexcitotoxicitymediates15,17 sublethalmyelininjuryanddeathof oligodendrocytesfromspinalcord." SOCIETYFORNEUROSCIENCEABSTRACTS,(1998) VOL.24,NO.1-2,PP.465.MEETINGINFO.: 28THANNUALMEETINGOFTHESOCIETYFOR NEUROSCIENCE,PARTLOSANGLES, CALIFORNIA,USANOVEMBER 7-12,1998 SOCIETYFORNEUROSCIENCE.,XP000874858 seeabstractparagraph2 X,PMATUTE:"characteristics ofacuteand1-11,14, chronickainateexcitotoxicity"15,17 PROC.NATL.ACAD.SCI.USA, vol.55,1998, pages10229-10234,XP000867876 seeabstractparagraph2 seeparagraph1-paragraph4 seeparagraph1-paragraph4;figures4,5 seepage10233,column2,paragraph4- paragraph4;figures4,5 P,XKIM,W.-G.ETAL:"AMPA/kainate receptor16 antagonistsreducelipopolysaccharide (LPS)/interferon-gamma(IFN-gamma)-induced neurotoxicityinmixedcortica neuronal/glialcellcultures." SOCIETYFORNEUROSCIENCEABSTRACTS,(1998) VOL.24,NO.1-2,PP.1857.MEETINGINFO.: 28THANNUALMEETINGOFTHESOCIETYFOR NEUROSCIENCE,PARTLOSANGELES, CALIFORNIA,USANOVEMBER7-12,1998 SOCIETYFORNEUROSCIENCE.,XP000884646 seeabstractparagraph4;figures4,5 /-- 8 INTERNATIONAL SEARCH REPORTtemational Application No PCT/GB99/02112 C.(Continuation) DOCUMENTS CONSIDEREDTOBERELEVANT Category ° Citation of document,withindication,whereappropriate,oftherelevantpessag es Relevant to olaim No. XMCDONALDJWETAL:"Oligodendrocytes 1-11,14, fromforebrainarehighlyvulnerableto15,17 AMPA/kainatereceptor-mediated excitotoxicity." NATUREMEDICINE,(1998MAR)4(3)291-7., XP000867881 Yseepage294,column2,paragraph2-12,13 paragraph4;figures4,5 seepage295,column2,paragraph3- paragraph4;figures4,5 XMATUTE:"glutamate receptor-mediated1-11,14, toxicity..."15,17 PROC.NATL.ACAD.SCI.USA, vol.94,1997, pages8830-8835,XP002130788 Yseeabstractparagraph4;figures4,512,13 seepage8832,column1-paragraph4; figures4,5 seepage8834,column1,paragraph1- paragraph4;figures4,5 seepage8834,column2,paragraph3- paragraph4;figures4,5 YDUSARTIETAL: Demyelination, and1-17 remyelinationbySchwanncellsand oligodendrocytesafterkainate-induced neuronaldepletioninthecentralnervous system." NEUROSCIENCE,(1992NOV)51(1)137-48., XP000874928 seepage140-paragraph4;figures4,5 seepage143-page144,paragraph4; figures4,5 XDE4239816A(INSTBIOANALYTIKGGMBH)115 June1994 Yseepage143-page144;claims1-3;12,13 figures4,5 seeabstract;claims1-3;figures4,5 XUS5750525A(HUTHANDREASETAL)1215 May1998 Yseecolumn2,line60-line67;figures1-11, 4,514-17 seecolumn3,paragraph3-line67; figures4,5 seecolumn3,paragraph3;claim3; figures4,5 8 8 I11'rERNATIONAL SEARCH REPORT Intert. _..nal Application No PCT/GB99/02112 C.(ContirsaUon)DOCUMENTSCONSIDEREDTOBERELEVANT _ _ Category ° Citation of documerH, with indication, where appropriate, of the rolavent passages Rekvant to alaim No. XUS5597809A(DREYEREVANB)28January 15 1997 Yseecolumn2;claim3;figures4,5 1-11, 14-17 seecolumn2;claim3;figures4,5;tables 3,9 XEP0492485A(GYOGYSZERKUTATOINTEZET)115 July1992 Yseepage13,line35-line55;figures1-11, 4,5;tables3,914-17 seeabstractline55;figures4,5;tables 3,9 XHEWETTSJETAL:"Potentiationof16 oxygen-glucosedeprivation-induced neuronaldeathafterinductionofiNOS." STROKE,(1996SEP)27(9)1586-91., XP000884364 seepage1586,column1,paragraph2- line55;figures4,5;tables3,9 seepage1588,column2,paragraph2,3- line55;figures4,5;tables3,9 XMILLERLGETAL:"Interleukin-116 modulatesGABAergicandglutamatergic functioninbrain." ANNALSOFTHENEWYORKACADEMYOF SCIENCES,(1994OCT31)739292-8., XP000884366 seepage294,paragraph3-line55; figures4,5;tables3,9 seepage294,paragraph3-line55; figure1C;tables3,9 A'MerckManual"5 1992XP00213078916 seepage1507,paragraph1-line55; figure1C;tables3,9 seepage1316,paragraph2-paragraph3; figure1C;tables3,9 8 InternationalapplicationNo. INTERNATIONALSEARCHREPORTPCT/GB99/02112 Box I Observationswherecertainclaimswerefoundunsearchable(Continua tionofitem1offirstsheet) ThisInternationalSearchReporthasnotbeenestablishedinrespecto fcertainclaimsunderArticle17(2)(a)forthefollowingreasons: 1.Claims Nos.: becausetheyrelatetosubjectmatternotrequiredtobesearchedbythi sAuthority,namely: 2.Nos. : becausetheyrelatetopartsoftheInternationalApplicationthatdon otcomplywiththeprescribedrequirementstosuch anextentthatnomeaningfulIntemationalSearchcanbecarriedout, specifically: seeFURTHERINFORMATIONsheetPCT/ISA/210 3.ClaimsNos.: becausetheyaredependentclaimsandarenotdraftedinaccordancewit hthesecondandthirdsentencesofRule64(a). Box II Observationswhereunityofinventionislacking(Continuationofite m2offirstsheet) ThisInternationalSearchingAuthorityfoundmultiple inventionsinthisinternationalapplication,asfollows: 1.As allrequiredadditionalsearchfeesweretimelypaidbytheapplicant, thisInternationalSearchReportcoversall searchableclaims. 2.n As all searchable claims couldbesearchedwithouteffortjustifyinganadditionalfee,thisAu thoritydidnotinvitepayment ofanyadditionalfee. 3.n As onlysomeoftherequiredadditionalsearchfeesweretimelypaidbythe appiicant,thisInternationalSearchReport coversonlythoseclaimsforwhichfeeswerepaid,specificallyclaims Nos.: 4._ Norequiredadditionalsearchfeesweretimelypaidbytheapplicant.C onsequently,thisInternationalSearchReportis restrictedtotheinventionfirstmentionedintheclaims;!iscovered byclaimsNos.: RemarkonProtestThe additfonatsearchfeeswereaccompaniedbytheapplicant'sprotest. g Noprotestaccompaniedthepaymentofadditionalsearchfees. u IntemationaiApplicationNo.PCT/GB99/02112 FURTHERINFORMATIONCONTINUEFROMPCT/ISA/210 Presentclaims relatetocompoundsdefinedbyreference toadesirablepharmacologicalproperty,namelytheactivityas antagonistofAMPA/kainatereceptor. Theclaimscoverallcompoundshavingthischaracteristicorproperty , whereastheapplicationprovidessupportwithinthemeaningofArticl e6 PCTand/ordisclosurewithinthemeaningofArticle5PCTforonlyavery limitednumberofsuchcompounds.Inthepresentcase,theclaimssolac k support,andtheapplicationsolacksdisclosure,thatameaningful searchoverthewholeoftheclaimedscopeisnotfullypossible. Independentoftheabovereasoning,theclaimsalsolackclarity(Arti cle 6PCT).Anattemptismadetodefinethecompoundsbyreferencetotheir pharmacologicalprofiles.Again,thislackofclarityinthepresentc ase issuchastorenderameaningfulsearchoverthewholeoftheclaimed scopeimpossible. Furthermore,presentclaim8relatestoanextremelylargenumberof possiblecompounds.SupportwithinthemeaningofArticle6PCTand/or disclosurewithinthemeaningofArticle5PCTistobefound,however, foronlyaverysmallproportionofthecompoundsclaimed.Inthepresen t case,theclaimsolackssupport,andtheapplicationsolacks disclosure,thatameaningfulsearchoverthewholeoftheclaimedscop e isimpossible. Consequently,thesearchhasbeencarriedoutforthosepartsofthe claimswhichappeartobeclear,supportedanddisclosed,namelythose partsrelatingtothecompoundsstructurallyidentifiedinclaims 9,12,13,16withdueregardtothegeneralideaunderlyingthepresent invention. Claimssearchedcompletely:9,12-13, Claimssearchedincompletely:1-8,10-11,14-17 INTERNATIONALSEARCHREPORT ItematfonaiApplieatlonNo InformaUononpatentfamilymembers 99/02112 PatentdocumentPublication Patent family citedinsearchreportdatemembers) date DE4239816A01-06-1994NONE US5750525A12-05-1998DE 4314591 A 09-02-1995 DE 4344486 A 22-06-1995 AU 690550 B 30-04-1998 AU 6675594 A 21-11-1994 CA 2161425 A 10-11-1994 CZ 9502828 A 14-02-1996 WO 9425469 A 10-11-1994 EP 0696288 A 14-02-1996 FI 955140 A 27-10-1995 HU 73676 A 30-09-1996 JP 8508037 T 27-08-1996 NO 954315 A 28-12-1995 NZ 265599 A 24-10-1997 PL 317075 A 03-03-1997 SK 131895 A 03-07-1996 US 5955461 A 21-09-1999 ZA 9402972 A 19-01-1995 US5597809A28-01-1997AU 711652 B 21-10-1999 AU 2819695 A 19-01-1996 CA 2192209 A 04-01-1996 EP 797442 A 1-10-1997 JP 10502340 T 03-03-1998 WO 9600073 A 04-01-1996 EP0492485A01-07-1992HU 59684 A 29-06-1992 US 5459137 A 17-10-1995 AT 160350 T 15-12-1997 AU 641578 B 23-09-1993 AU 8996391 A 25-06-1992 CA 2057504 A 22-06-1992 CN 1062730 A, B 15-07-1992 CN 1191111 A 26-08-1998 CZ 9103985 A 19-01-1994 DE 69128236 D 02-01-1998 DE 69128236 T 14-05-1998 ES 2112848 T 16-04-1998 FI 916032 A 22-06-1992 GR 3026127 T 29-05-1998 IL 100449 A 31-12-1995 JP 2756742 B 25-05-1998 JP 5070463 A 23-03-1993 KR 169134 B 15-01-1999 MX 912734 A 1-Q6-1992 NO 300376 8 20-05-1997 NZ 241110 A 27-04-1994 SI 9111966 A 30-04-1995 US 5604223 A 18-02-1997 US 5536832 A 16-07-1996 US 5519019 A 21-05-1996 US 5521174 A 28-05-1996 US 5639751 A 17-06-1997 ZA 9110064 A 28-10-1992



 
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