IE45454B1 - Pharmaceutical compositions having an action on the central nervous system - Google Patents

Pharmaceutical compositions having an action on the central nervous system

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Publication number
IE45454B1
IE45454B1 IE1509/77A IE150977A IE45454B1 IE 45454 B1 IE45454 B1 IE 45454B1 IE 1509/77 A IE1509/77 A IE 1509/77A IE 150977 A IE150977 A IE 150977A IE 45454 B1 IE45454 B1 IE 45454B1
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IE
Ireland
Prior art keywords
pharmaceutical composition
composition according
hydroxy
fluoro
alkyl
Prior art date
Application number
IE1509/77A
Other versions
IE45454L (en
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Synthelabo
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Publication date
Priority claimed from FR7622045A external-priority patent/FR2358881A1/en
Priority claimed from FR7719390A external-priority patent/FR2453643A2/en
Application filed by Synthelabo filed Critical Synthelabo
Publication of IE45454L publication Critical patent/IE45454L/en
Publication of IE45454B1 publication Critical patent/IE45454B1/en

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)

Abstract

PHARMACEUTICAL COMPOSITIONS HAVING AN ACTION ON THE CENTRAL NERVOUS SYSTEM The specification discloses pharmaceutical compositions, having an action on the central nervous system, containing a gabamimetic compound and a neuroleptic compound. The gabamimetic compound has the formula and the neuroleptic compound has the formula The compositions of the invention are medicaments which can be used in human therapy in the psychiatric field and, in particular, in the treatment of psychosis.

Description

The present invention relates to pharmaceutical compositions, having an action on the central nervous system, containing a gabamimetic compound and a neuroleptic compound.
The gabamimetic compound used in the compositions of the present invention is a compound of Patent Specification No.. 43143, corresponding to the formula? . in which X^ x2 and X3, which are identical or different, each represent hydrogen, halogen, especially chlorine or fluorine, methyl or methoxy, n is an integer from 1 to 10, and R represents -OH, -NH2, -NH(CH2)3~COOH, 0M or -NH(CH2)3-COOM Where M represents an alkali metal atom, in particular a sodium atom), «-NC(CH2) g-COOCjHg, -NH-cycloalkyl, -NH-phenyl, -NH-benzyl or -tJ- (alkyl) benzyl2, the saia alkyls being linear or branched, and containing from - 2 1 to 4 carbon atoms each and the 3aid cyeloalkyl radicals containing from 3 to 6 carbon atoms, provided that when X-^ and X3 both represent hydrogen, a is 1, and R is OH, Xg is not chlorine in the 5-position.
The neuroleptic compound is chosen from Haloperidol, '*·! - rp; oniazine. Thioridazine, Clozapine, Sulpiride ,·.ηά the derivatives of 2-methoxybenzoic acid, described in Patent Specification No. 2731/75 and British Patent Specification No. 1,556,566 in the form of their racemates or their optical isomers, of the formula: och3 i3 N - CH. Λ/2’ (IX) in which n is 1 or 2, Rj represents a cycloalkyl-alkyl radical of formula: Wm -CH-Aor a phenylalkyl radical of formula in which m represents an integer fro$ 2-5, A is a linear or branched alkylene chain containing to 4 carbon atoms and R^, and Rg each represent hydrogen, halogen, in particular fluorine and chlorine, trifluoromethyl, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms: CNCHj-CHg-, CHSC-CHg- , n represents 1 or 2, Rg represents chlorine,-SOgRg, Rg being alkyl of 1 to 4 carbon atoms» or-SOgNRgR? where Rg and Ry, which are identical or different» each represent hydrogen or alkyl of 1 to 4 carbon atoms; and Rg represents hydrogen or alkyl of 1 to 4 carbon atoms.
More particularly, the pharmaceutical compositions of the invention contain, as the gabamimetic compound, one of the following compounds of formula I: sodium N-(a-phtenyl-5-fluoro-2-hydroxybenzylidenyl)-4-aminobutyrate (SL 75,010), sodium N-[a(4-chlorophenyl)-5fluoro-2-hydroxybenzylidenyl]-4-amino-butyrate (SL 75,102), N-[a-(4-chlorophenyl)-5-fluoro-2-hydroxybanzylidenyl]-4-amino-butyramide (SL 76,002) and N-[ More particularly, the compositions of the invention contain, as the neuroleptic, Haloperidol, Chlorpromazine or the preferred compound of formula II viz.
K- [1-(p-fluorobenzyl)-pyrrolidinyl-2-methyl]-2-methoxy-5sulphameyl-benzamide (SL 74,205) in the form of the racemate or an optical isomer. - 4 Preferred compositions according to this invention are those containing Haloperidol and sodium N-(a-phenyl-5-fluoro-2hydroxy-benzyliaenyl)-4-amino-butyrate, Haloperidol and sodium [y,„ /4-chlorophenyl)-5-fluoro-2-hydroxy-benzylidenylJ-4-amino5 Outyratf, Haloperidol —id 14-[a·· (4-chlorophenyl)-5-fluoro-2-hydrox„ benzylidenylj-4-amino-butyramide, Haloperidol and N-fc-phenyl-5fluoro-2-hydroxy-benzylidenylj-4-amino-butyramide, Chlorpromazine and sodium N-(u-phenyl-5-fluoro-2-hydroxybenzylidenyl)-4-aminobutyrate, Chlorpromazine and sodium N-Ca-(4-chlorophenyl)-5--0 fluoro-2-hydroxy-benzylidenylJ - 4-amino-butyrate, Chlorpromazine and N-C«-(4~ehlorophenyl)-5-£luoro-2-hydroxy~benzylidenyl]-4-aminobutyramide, N-[l-(p-£luorobenzyl)-pyrrolidinyl-2-methyl0-2-methoxy5-sulpnamoyl-benzamide in thv form of the optical Isomer (R) and sodium Η-Cot-(4-chiorophenyli-5-fluoro-2-nydroxy-benzylideny3-415 amino-butyrate, or N-£l- (p-fluorobenzyl) -pyrrolidinyl-2-methyjJ-2 methoxy-E-sulphamoyi-benzamide in the form of the optical isomer (R) and Κ-Γα(4-chlorophenyl)-5-fluoro-2-hydroxy-benzylidenylQ-4amino-butyramide. Preferably, the compositions will contain from 5 to 50 parts by weight of the neuroleptic compound and from 10 to 100 parts by weight of the gabamimetic compound. - 5 The pharmaceutical compositions of the invention are medicaments which can be used iii human therapy in the psychiatric field and. in particular, in the treatment f of psychoses (for example schizophrenia).
It has been shown: 1. That there exists a GABAergic inhibitory control of the mesolimbic dopaminergic neurons (K. FUSS and colleagues, Med. Biol. 1975. 53, 177-183; M. PEREZ de la MORA and colleagues. Neurosc. Let. 1975. 1, 109-114); 2. that neuroleptics, in particular Haloperidol, which are blocking agents of the central dopaminergic receptors inhibit the recapture of γ-aminobutyric acid (GABA) (L.L. IVERSEN and colleagues, J. Neurochem. 1971, 12, 1939-1950) and increase the turn over of GABA (G.G.S. COLLINS Biochem. Pharmacol. 1973 22, 101-111); 3. that GABA suppresses the effects of dopamine or f apomorphine injected directly into the caudate nucleus in cats (A. R. COOLS and colleagues, J. Pharm. Pharmacol. 1976, 28, 70-74); and 4. that the inhibitors of GABA-transaminase potentiate the cataleptic activity of the neuroleptics in rats (W. HAEFELY and colleagues, Psyeho-pharmacol. Bull. 1975, 11, No. 4, 58-59; and H.H. KELLER and colleagues, Arch. Pharmacol. 1976, 293, 34 R 9).
Tests made on the compositions of the invention - 6 45 4 5 4 have sought to discover whether the gabamimetic derivatives mentioned above potentiate the cataleptigenic activity of the indicated neuroleptics.
The experimental procedure used was a modification of that described by D. H. Tedeschi and colleagues (Arch. fat. Pharmacodyn, 1959-122 - 129-143). i1) Potentiation of catalepsy induced by Haloperidol (Table 1) The rats receive, intraperitoneally. either the solvent (solution containing 1% by waight of Polysorbate 80 in distilled water) (control batch) or the GABA-mimetic studied.
Immediately afterwards, the animals receive Haloperidol intraperitoneally at a dose of 0.15 to 0.30 or 0.60 mg/kg. Tha p-esence or absence of catalepsy is investigated, by the so-called rubber bung method, , 30, 60, 90 and 120 minutes after the injection of Haloperidol. The average percentage of positive observations i.s then calculated for each treatment.
The statistical significance of the results is evaluated by the Xruskall-Wallis test for the analysis of the nonparametric variance. The results are given in Table 1 whieh follows! - 7 4.S4S4 Kruskall-Wallis test Potentiation of catalepsy induced by the compound Sl· 74.205 The rats receive, intraperitoneally. either the solvent (solution containing 1% of Polysorbate 80 in distilled water) (control batch) or the GABA-mimetic studied. Immediately afterwards the animals receive the compound 74,205, intraperitoneally, at a dose of 50, 100 cr 200 mg/kg.
The presence or absence of catalepsy is investigated, by the so-called rubber bung method, bO, 90, 120, 150 and 180 minutes after the injection of the compound 74,205. The Average percentage of positive observations is then calculated for each treatment.
The statistical significance of the results is evaluated by the Kruskall-Wallis test for the'analysis of the non15 parametric variance. The results are given in Table 2 which follows. •Λ Ο CM •ί 200 * * 10 Γ- 10 [69.8+8* b- + * ώ * * ο Ο +1 οο «Η +> Ο Η «3 ¥r Ο Ch • ΙΑ CM ? ιη Η «*« • • Α CM ο +1 +1 Ο ιη m t- • • CM an TABLE 2 .ο •Η +> Λ Φ ηί Ο Ή Ο X Λ1 ω«ί <8 β) boo C Β+> Ο Ή Η β» ti Μ 10 Ο & •ϋ η) Ί Ο Ο Η ΦΟ (0 ο Ό Η Φ (β β ωο °·^ S ^bS° S ·Η Ο h ο ω ω wrap, »o « 4tJC. C- +> 8 CO <5' ίΛ Η' (υ S' .<(· Η ΙΛ 3· • Μ Η Kruskall-Wallis test ηι ΙΛ Ν Ο Ο * M3 CΙΑ Η Ο Ο • · Ο Ο V V 0. 8, * £ - 10 Potentiation of catalepsy induced by Chlorpromazine The method differs from the preceding only in the fact that Chlorpromazine (CPZ) is adminstered intraperitoneally ac doses of 3. 6 and 9 mg/kg.
The results are ewen in Table 3 below. - 11 « rd <ϋ a Ή cn 8 +1 CM m 51 ±4.4** 68.5+5.3** VO • co 41 • CM 22.3+4.8** +1 ro • 00 CM tn o 4· • tn • ΪΜ | O •rt •P Λ •φ flj O ^d o o •rt •P ω S 0 sS Λ bO H Μ H o o o \ I CO in o o bOtO (U rd rd H i-t.fi +> o Φ o Φ o 4) at c-p IQ ω W W'rt'H O o O O p Ό Ό •a -a CM tn cS' cn tn tn tn +1 in tn CM in +i o tn VO tn +i tn tn ‘ίι tn CM CM K\ +i • CM rd tn tn -3' SA CM tn o +» Φ tn tCM ·» CM o o -JI P, P, * « The results reported above demonstrate a potentiation of the effect of the neuroleptics by the gabamimefcic compounds.
The combination according to the invention thus 5 makes it possible to reduce the neuroleptic dose. In fact, in animals. in spite of using· a liminal cataleptigenic dose of neuroleptic, a marked cataleptic activity of the combinations studied is observed.
For human or veterinary administrations, the 10 combinations of gabamimetics and neuroleptics are presented in the forms appropriate for oral, enteral or parenteral use.
By way of example, it can be indicated that the daily dosage will be from 50 to 500 mg. of chlorpromazine associated with 100 mg to 1 g of the gabamimetic compound.
The compositions may be made up in conventional manner using known carriers and adjuvants compatible with tne active ingredients.

Claims (16)

CLAIMS:
1. A pharmaceutical composition containing: (1) a gabamimetic compound of the general formula: in which X^, X 2 and X^, which are identical or different, each represent hydrogen, halogen,methyl, or methoxy, n is an integer from 1 to 10, and R represents -OH, -NH 2 , -HH(CH 2 ) 3 -COOH, OM or - HH(CH 2 ) 3 ~CCOM (where M'represents an alkali metal), -NC(CH 2 ) 3 ~COOC 2 H 5 , -NH-cycloalkyl, -NH-phenyl, -NH-b'enzyl or N-(alkyl)benzyl (the benzyl being unsubstituted or substituted by one or more substituents chosen from halogen atoms and trifluoromethyl),-NH-alkyl, or -N(alkyl)^, the said alkyls being linear or branched and contaihing from 1 to 4 carbon atoms each and the said cycloalkyl radicals containing from 3 to 6 carbon atoms each, provided that when X 1 and X 3 both represent hydrogen, n is 1, R is OH, X 2 is not a chlorine atom in the 5-position. 14 and (2) a neuroleptic compound which is Haloperidol, Chlorpromazine, Thioridazine, Clozapine, Sulpiride or a derivative of 2-methoxybenzoic acid, in the form of a racemate or optical isomer, of the formula: .5 OCHg in which n is 1 or 2, represents a cycloalkyl-alkyl radical of formula: (CH.) ?6 J} or a phenylalkyl radical of the formula 5 in which . o r 4 Am represents an integer from 2 to 5, A is a linear or branched alkylene chain containing 1 to 4 carbon atoms and R 4 , R g and R g each repjreaent hydrogen, halogen, trifluoromethyl, alkyl of 1 to 3 carbon atoms, or alkoxy of 1 to 3 carbon atoms, cnch 2 -ch 2 , ch s c-ch 2 -, - 15 455454 R^ represents chlorine, -SOjR^, where Rg is alkyl of 1 to 4 carbon atoms, or -SOgNRgRy, where R g and Ry, which are identical or different, each represent hydrogen or alkyl of 1 to 4 carbon atoms: and 5 represents hydrogen or alkyl of 1 to 4 carbon atoms.
2. A pharmaceutical composition according to claim 1, in which the neuroleptic compound is Haloperidol, Chloipromaaine or N-[l-(E-fluorobenzyl)-pyrrolidinyl-2methyl]-2-methoxy-5-sulphamoyl-benzamide. i_q
3. A pharmaceutical composition according to claim 1 or claim 2, in which the gabamimetic compound is sodium N-(a-phenyl-’5-fluoro-2-hydroxy-benzylidenyl)-4amino-butyrate, sodium N-[a-(4-chlorophenyl)-5-fluoro2-hydroxy-benaylidenyl]-4-amino-butyrate, N-[a-(415 chlorophenyl)-5-fluoro-2-hydroxy-benzylidenyl]-4-aminobutyramide, or N-[e-phenyl-5-fluoro-2-hydroxy-benzylidenyl] 4. -amino-butyramide.
4. A pharmaceutical composition according to claim 1 containing Haloperidol and sodium H-(a-phenyl-5 20 fluoro-2-hydroxy-benzylidenyl)-4-amino-butyrate. - 16 ύΰ-15 4
5. A pharmaceutical composition according to claim 1 containing Haloperidol and sodium N-[a-(4chlorophenyl)-5-fIvoro-2-hydroxy-benzylidenyl]-4-aminobutyrate.
6. A pharmaceutical composition according to claim 1 containing Haloperidol and N-[a-{4-chlorophenyl )-5-fluoro- ; -hydroxy-benzylidenylJ-4-aminofoutyramide.
7. A pharmaceutical composition according to claim 1 containing Haloperidol and N-[a-phenyl-5~fluoro2-hydroxy-benzylj denylj-4-amino-butyramide.
8. A pharmaceutical composition according to claim 1 containing Chlorpromazine and sodium N-(a-phenyl5-fluoro-2-hydroxy-benzyli denyl)-4-amino-butyrate.
9. A pharmaceutical composition according to claim 1 containing chlorpromazine and sodium N-[a-(4chlorophenyl)-5-fiuor o~2-hydroxy-benzylidenyl]-4-aminobutyrate.
10. A pharmaceutical composition according to claim 1 containing Chlorpromazine and N-[«-(4-chlorophenyl)5-fluoro-2-hydroxy-benzylidenyl]-4-amino-butyramide.
11. A pharmaceutical composition according to claim 1 containing N-[l-(£-£luorobenzyl)-pyrrolidinyl2-methyl]“2-methoxy-5-sulphamoyl-benzamide in the form of the optical isomer (R) and sodium N-[a-(4-chlorophenyl)-5-fluoro-2-hydroxy~benzylidenyl]-4-amino-butyrate. '
12. A pharmaceutical composition according to claim 1 containing N-jl-(p-fluorobenzyl)-pyrrolidinyl-2-methyl]-2-methoxy5-sulphamoyl-benzamide in the form of the optical isomer (R) and N-[a-(4-chlorophenyl)-5-fluoro-2-hydroxylbenzylidenyl| -4-amino-butyramide,
13. A pharmaceutical composition according to claim 1 wherein the neuroleptic compound (2) is Sulpiride or Clozapine or said derivative of formula (II) wherein is said phenylalkyl radical and R^, Rg and R g are selected from halogen, trifluoromethyl, C^-Cg alkyl, and C^—Cg alkoxy, and R g may additionally be hydrogen.
14. A pharmaceutical composition according to claim 1, wherein the neuoleptic compound (2) is Haloperidol, Chlorpromazine, Thioridazine, Sulpiride, or said derivative of formula (II) wherein Rg and R g in the definition of R^ are both hydrogen.
15. A pharmaceutical composition according to any of the preceding claims containing from 5 to 50 parts by weight of the neuroleptic compound and from 10 to 100 parts by weight of the gabamimetic compound.
16. A pharmaceutical composition according to claim 1 substantially as hereinbefore described.
IE1509/77A 1976-07-20 1977-07-19 Pharmaceutical compositions having an action on the central nervous system IE45454B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7622045A FR2358881A1 (en) 1976-07-20 1976-07-20 Neuroleptic compsn. contg. a gabamimetic potentiator - which is a benzylidene-amino-alkanoic acid deriv., for treating e.g. schizophrenia
FR7719390A FR2453643A2 (en) 1977-06-24 1977-06-24 PHARMACEUTICAL COMPOSITIONS ACTIVE ON THE CENTRAL NERVOUS SYSTEM

Publications (2)

Publication Number Publication Date
IE45454L IE45454L (en) 1978-01-20
IE45454B1 true IE45454B1 (en) 1982-08-25

Family

ID=26219550

Family Applications (1)

Application Number Title Priority Date Filing Date
IE1509/77A IE45454B1 (en) 1976-07-20 1977-07-19 Pharmaceutical compositions having an action on the central nervous system

Country Status (11)

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JP (1) JPS5326327A (en)
AU (1) AU508753B2 (en)
CA (1) CA1077846A (en)
DE (1) DE2732614A1 (en)
GB (1) GB1556567A (en)
IE (1) IE45454B1 (en)
IL (1) IL52550A (en)
LU (1) LU77796A1 (en)
NL (1) NL7708055A (en)
NZ (1) NZ184666A (en)
SE (1) SE7708349L (en)

Also Published As

Publication number Publication date
SE7708349L (en) 1978-01-21
CA1077846A (en) 1980-05-20
IE45454L (en) 1978-01-20
JPS5326327A (en) 1978-03-11
NL7708055A (en) 1978-01-24
AU2715177A (en) 1979-01-25
DE2732614A1 (en) 1978-01-26
LU77796A1 (en) 1977-10-25
IL52550A (en) 1981-03-31
AU508753B2 (en) 1980-04-03
IL52550A0 (en) 1977-10-31
GB1556567A (en) 1979-11-28
NZ184666A (en) 1980-04-28

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