NL8302435A - SYNERGISTIC ANTIHYPERTENSIVE PHARMACEUTICAL COMPOSITION. - Google Patents
SYNERGISTIC ANTIHYPERTENSIVE PHARMACEUTICAL COMPOSITION. Download PDFInfo
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- NL8302435A NL8302435A NL8302435A NL8302435A NL8302435A NL 8302435 A NL8302435 A NL 8302435A NL 8302435 A NL8302435 A NL 8302435A NL 8302435 A NL8302435 A NL 8302435A NL 8302435 A NL8302435 A NL 8302435A
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- pharmaceutical composition
- indapamide
- thiachroman
- butylamino
- tert
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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
- A61K31/40—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
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- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
N/31.521-kp/Pf/cs * *N / 31.521-kp / Pf / cs * *
Synergistische antihypertensieve farmaceutische samenstelling.Synergistic antihypertensive pharmaceutical composition.
De onderhavige uitvinding heeft betrekking op een farmaceutische samenstelling, welke een combinatie van twee actieve stoffen, indapamide en 8-(3-tert-butylamino-2-hydroxy-propoxy)thiachroman omvat.The present invention relates to a pharmaceutical composition comprising a combination of two active substances, indapamide and 8- (3-tert-butylamino-2-hydroxy-propoxy) thiachroman.
5 Indapamide, of N-(3-sulfamoyl-4-chloorbenzamido)-2- methylindoline, of ook 4-chloor-N-(2-methyl-l-indolinyl)-3-sulfamoylbensamide, is beschreven in voorbeeld I van het Franse octrooischrift No. 69.06023 (gepubliceerd onder No. 2.003.311) als een diureticum dat in het bijzonder voor de be-10 handeling van arteriële hypertensie gebruikt kan worden.Indapamide, or N- (3-sulfamoyl-4-chlorobenzamido) -2-methylindoline, or also 4-chloro-N- (2-methyl-1-indolinyl) -3-sulfamoyl bensamide, is described in Example I of the French Patent No. 69,06023 (published under No. 2,003,311) as a diuretic which can be used particularly for the treatment of arterial hypertension.
8-(3-tert-Butylamino-2-hydroxypropoxy)thiachroman (of de additiezouten ervan) is beschreven in voorbeeld II van het Franse octrooischrift No. 71.11445 (gepubliceerd onder No. 2.092.004), waarin de cardiovasculaire eigenschappen, in het 15 bijzonder beta-blokkerende eigenschappen worden vermeld.8- (3-tert-Butylamino-2-hydroxypropoxy) thiachroman (or its addition salts) is described in Example II of French Pat. 71,11445 (published under No. 2,092,004), which lists cardiovascular properties, in particular beta-blocking properties.
Thans werd echter gevonden, dat de twee bovengenoemde verbindingen wanneer toegepast in combinatie, onverwachte synergistische eigenschappen hebben, hetgeen een gelijktijdig therapeutisch gebruik mogelijk maakt.However, it has now been found that the above two compounds when used in combination have unexpected synergistic properties, allowing for simultaneous therapeutic use.
20 De uitvinding heeft dan ook betrekking op een farma ceutische samenstelling, welke een combinatie van indapamide en 8-(3-tert-butylamino-2-hydroxypropoxy)thiachroman, of een van de farmaceutisch aanvaardbare additiezouten daarvan, bevat, waarbij het mogelijk is dat ieder van deze twee verbin-25 dingen dan wel in de racemische vorm of in de vorm van een optisch isomeer is, alsmede tevens een therapeutisch geschikt hulpmiddel of drager.The invention therefore relates to a pharmaceutical composition containing a combination of indapamide and 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman, or one of its pharmaceutically acceptable addition salts, it being possible that each of these two compounds is either in the racemic form or in the form of an optical isomer, as well as a therapeutically suitable vehicle or carrier.
Gemakshalve zal 8-(3-tert-butylamino-2-hydroxypro-poxy)thiachroman in het vervolg worden aangeduid als "THPT".For convenience, 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman will hereinafter be referred to as "THPT".
30 Farmacologische studie.30 Pharmacological study.
De volgens de uitvinding bestudeerde verbindingen werden alleen en in combinatie beproefd op functionele remming van membraanadenylaatcyclase.The compounds studied according to the invention were tested alone and in combination for functional inhibition of membrane adenylate cyclase.
De rode bloedlichaampjes van duiven staan bekend om 35 hun aanzienlijke adenylaatcyclaseactiviteit sedert de studies van Sutherland e.a. (Adenylcyclase 1. Distribution, preparation and properties, J. Biol. Chem. (1962) 237 : 1220-1227). De 8302435 - 2 - \Pigeons' red blood cells are known for their significant adenylate cyclase activity since the studies of Sutherland et al. (Adenylcyclase 1. Distribution, preparation and properties, J. Biol. Chem. (1962) 237: 1220-1227). The 8302435 - 2 - \
M WM W
experimenten werden uitgevoerd op schimmen van erythrocyten (open cellen) die waren bereid uit het bloed van Strasser-duiven volgens de werkwijze van Salesse R. en Gamier J., "Invloeden van geneesmiddelen op erythrocytmembraan van duiven 5 en asymmetrische regeling van adenylaatcyclase door de lipide-dubbellaag" (Biochem. Biophys. Acta (1979) 554 : 102-103).experiments were performed on shades of erythrocytes (open cells) prepared from the blood of Strasser pigeons according to the method of Salesse R. and Gamier J., "Influences of drugs on erythrocyte membrane of pigeons and asymmetric regulation of adenylate cyclase by the lipid bilayer "(Biochem. Biophys. Acta (1979) 554: 102-103).
De verkregen suspensies werden gedurende 20 min geïn-cubeerd in een hypotonische buffer met een volume van het beproefde product in de gewenste eindconcentratie. De adenylaat-10 cyclaseactiviteit werd bepaald volgens de methode van Bern-baumer L. e.a. (J. Biol. Chem. (1969) 244 : 2468-2476); en Ramachandran J., Lee V. (Biochem. Biophys. Res. Commun. (1970) 41 : 358-366).The resulting suspensions were incubated for 20 min in a hypotonic buffer with a volume of the tested product at the desired final concentration. The adenylate-10 cyclase activity was determined by the method of Bernbaumer L. et al. (J. Biol. Chem. (1969) 244: 2468-2476); and Ramachandran J., Lee V. (Biochem. Biophys. Res. Commun. (1970) 41: 358-366).
De eindconcentraties aan reagentia waren ATP 2 mM met 15 1 j^Ci aan [a- j]P ATP, theofylline 4 mM, fosfocreatine 10 mM, creatinekinase 0,5 g/1, MgCl2 7,5 mM, tromethamine HC1 ("TRIS" HC1) 10 mM, pH = 7,4.Final reagent concentrations were ATP 2 mM with 15 1 µCi of [a-j] P ATP, theophylline 4 mM, phosphocreatine 10 mM, creatine kinase 0.5 g / 1, MgCl 2 7.5 mM, tromethamine HCl ("TRIS "HCl) 10 mM, pH = 7.4.
Het totale volume bedroeg 75 ul en het aantal cellen O ' per buis was ongeveer 10 .The total volume was 75 µl and the number of cells O 'per tube was about 10.
20 De productie van cyclisch AMP (cAMP) werd gestimu leerd door hetzij 0,05 mM isoproterenol in aanwezigheid van 0,1 mM GTP, hetzij 10 mM natriumfluoride. De verbinding werd toegevoegd tot aan de vereiste eindconcentratie.The production of cyclic AMP (cAMP) was stimulated by either 0.05 mM isoproterenol in the presence of 0.1 mM GTP or 10 mM sodium fluoride. The compound was added to the required final concentration.
De reactie werd na 15 min bij 37°C gestopt door toe-25 voeging van 300 jjlI 0,5 N zoutzuur en door het mengsel gedurende 3 min boven een kokend waterbad te plaatsen. De buizen werden daarop verwijderd uit het waterbad en de inhoud werd geneutraliseerd door 300 )Al 1,65 N imidazool.The reaction was stopped after 15 min at 37 ° C by adding 300 µl 0.5 N hydrochloric acid and placing the mixture over a boiling water bath for 3 min. The tubes were then removed from the water bath and the contents were neutralized by 300 µl of 1.65 N imidazole.
Na centrifugering (10 min, 4000x g) , werd 500 ja.1 van 39 de bovenstaande vloeistof gebracht op een neutrale kolom van geactiveerd alumina en geëlueerd met 2,6 ml imidazool, 10 mM, pH = 7,5. Deze kolommen gaven een opbrengst aan cAMP van 95%.After centrifugation (10 min, 4000x g), 500 ml of the supernatant was applied to a neutral column of activated alumina and eluted with 2.6 ml imidazole, 10 mM, pH 7.5. These columns gave a 95% yield of cAMP.
De radioactiviteit van de monsters werd gemeten in een scintillatieteller "Packard Tricarb", onder toepassing van 35 het Cerenkoveffect na toevoeging van 10 ml 1% waterige oplossing van 7-amino-l,3-naftaleendisulfonzuur aan het eluaat (tellingsopbrengst 65%).The radioactivity of the samples was measured in a "Packard Tricarb" scintillation counter, using the Cerenkov effect after adding 10 ml of 1% aqueous solution of 7-amino-1,3-naphthalenedisulfonic acid to the eluate (count yield 65%).
Volgens een logarithmische schaal werden drie concentraties boven en drie concentraties onder die concentratie be- 8302435 ' * .......... ** - 3 - paald, waarvoor, in vitro, op de darmscheelslagader van ratten een remming van de helft van de door noradrenaline geïnduceerde vasoconstrictie kon worden waargenomen.On a logarithmic scale, three concentrations above and three concentrations below that concentration were determined 8302435 * .......... ** - 3, for which, in vitro, inhibition of the rat intestinal artery was performed. Half of the norepinephrine-induced vasoconstriction could be observed.
De resultaten worden gegeven als het gemiddelde van 5 drie proeven in pmol cyclisch AMP geproduceerd per min en per mg membraanfosfolipides.The results are given as the average of 5 three experiments in pmol of cyclic AMP produced per min and per mg of membrane phospholipids.
Gezien kan worden, dat het in deze proef gebruikte indapamide en THPT de door isoproterenol of natriumchloride gestimuleerde activering van adenylaatcyclase remde: de hoe-10 veelheid geproduceerd cAMP neemt af. De aard van het effect op de productie van cAMP, als waargenomen, hangt af van de concentratie van de gebruikte verbinding. De actieve concentratie van iedere verbinding welke een remming van 25% (AC25) resp.It can be seen that the indapamide and THPT used in this experiment inhibited isoproterenol or sodium chloride-stimulated activation of adenylate cyclase: the amount of cAMP produced decreases. The nature of the effect on cAMP production, as observed, depends on the concentration of the compound used. The active concentration of each compound which has an inhibition of 25% (AC25) resp.
50% (ACjjq) oplevert, werd grafisch bepaald en vervolgens die 15 van de mengsels ervan bij de betrokken concentraties: -550% (ACjjq) was determined graphically and then those 15 of their mixtures at the concentrations involved: -5
Indapamide (mol.gew. = 365,89): AC^ = 9 x 10 mol/1 AC5q = 3 x 10”4 mol/1 THPT HC1 (mol.gew. = 331,90): AC25 = 1,2 x 10~5 mol/1 AC5q = 7 x 10"5 mol/1 20 De volgende tabel geeft het bereikte percentage rem ming met ieder van de vier mengsels van de twee verbindingen bij deze concentraties:Indapamide (mol. Wt. = 365.89): AC ^ = 9 x 10 mol / 1 AC5q = 3 x 10 "4 mol / 1 THPT HCl (mol. Wt. = 331.90): AC25 = 1.2 x 10 ~ 5 mol / 1 AC5q = 7 x 10 "5 mol / 1 20 The following table shows the percent inhibition achieved with each of the four mixtures of the two compounds at these concentrations:
TABELTABLE
Indapamide 25% Indapamide 50% 25 THPT 25% 45% 62% THPT 50% 62% 75%Indapamide 25% Indapamide 50% 25 THPT 25% 45% 62% THPT 50% 62% 75%
Gezien kan worden, dat de met het mengsel van de twee verbindingen bereikte remming duidelijk aanzienlijk beter is dan die welke werd bereikt met ieder van de verbindingen apart.It can be seen that the inhibition achieved with the mixture of the two compounds is clearly significantly better than that achieved with each of the compounds separately.
-5 30 Met een mengsel met de concentraties van 9 x 10 mol/1 aan -5 indapamide en 1,2 x 10 mol/1 aan THPT werd bijvoorbeeld 45% -4 remming bereikt, hetgeen slechts haalbaar is met 2,5 x 10 -5 mol/1 indapamide of met 5 x 10 mol/1 THPT, dat wil zeggen ongeveer 3 tot 4 maal de noodzakelijke hoeveelheid van ieder 35 van de verbindingen wanneer apart genomen. De twee effecten <9302 43 5 - 4 - s v W- die overeenkomen met 45% remming worden dan ook wat betreft hun globale effect vermenigvuldigd en leiden tot een remming van 45% van de activiteit van het enzym.-5 With a mixture with the concentrations of 9 x 10 mol / l to -5 indapamide and 1.2 x 10 mol / l to THPT, for example 45% -4 inhibition was achieved, which is only achievable with 2.5 x 10 -5 mol / 1 indapamide or with 5 x 10 mol / 1 THPT, i.e. about 3 to 4 times the necessary amount of each 35 of the compounds when taken separately. The two effects <9302 43 5 - 4 - s v W- corresponding to 45% inhibition are therefore multiplied in their global effect and lead to an inhibition of 45% of the activity of the enzyme.
Discussie; 5 Aangezien THPT bekend is als een beta-blokkeringsmid- del, kon zijn remmende werking op adenylcyclase in combinatie met een extracellulaire beta-receptor worden voorzien. Daarentegen kon niet worden verwacht dat een anti-hypertensief di-ureticum, zoals indapamide, een soortgelijke activiteit zou 10 hebben en dat, bovenal, de activiteit van deze twee verbindingen gecombineerd zou worden: in feite toont de dosis/acti-viteits-curve van deze verbindingen, en in het bijzonder hun AC22 en AC^q, dat zij in een vermenigvuldigend synergetismé werken.Discussion; Since THPT is known as a beta blocking agent, its inhibitory effect on adenyl cyclase in combination with an extracellular beta receptor could be foreseen. In contrast, an anti-hypertensive diuretic, such as indapamide, could not be expected to have a similar activity and, above all, the activity of these two compounds would be combined: in fact, the dose / activity curve of these compounds, and in particular their AC22 and AC ^ q, act in a multiplying synergism.
15 cAMP is een tweede intracellulaire boodschapper, die de start van cellulaire functies in gang zet. Door adenylcyclase te remmen worden alle toestanden van cellulaire hyperactiviteit, zoals die welke bestaan bij hyperactiviteit van de schildklier, hypertensie, hypergevoeligheid, enzovoort, 20 vertraagd. Als resultaat wordt de combinatie van de twee verbindingen, die volgens de uitvinding synergetisch werken, in het bijzonder geïndiceerd voor de behandeling van toestanden van beta-afhankelijke hyperactiviteit, zoals deze worden tegengekomen bij hypertensie, in het bijzonder in het geval 25 van ernstige arteriële hypertensie tezamen met nierafwijkingen of bij gebreken, zoals hyperactiviteit, aan de schildklier.CAMP is a second intracellular messenger that initiates the initiation of cellular functions. By inhibiting adenyl cyclase, all states of cellular hyperactivity, such as those that exist with thyroid hyperactivity, hypertension, hypersensitivity, etc., are delayed. As a result, the combination of the two compounds, which act synergistically in accordance with the invention, is particularly indicated for the treatment of beta-dependent hyperactivity states, such as encountered in hypertension, especially in the case of severe arterial hypertension together with kidney abnormalities or deficiencies, such as hyperactivity, of the thyroid gland.
De farmaceutische samenstellingen volgens de uitvinding worden bij voorkeur langs orale weg toegediend en kunnen 30 de vorm aannemen van tabletten, beklede tabletten, capsules, suspensie, enzovoort. Zij kunnen in het bijzonder 0,8-3 mg indapamide en 3-12 mg THPT of een van de farmaceutische aanvaardbare additiezouten daarvan bevatten, alsmede de hulpmiddelen of dragers die voor orale toedieningsvormen gebruikelijk 35 zijn, en zij kunnen worden toegediend in een of twee dagelijkse doses.The pharmaceutical compositions of the invention are preferably administered orally and may take the form of tablets, coated tablets, capsules, suspension, etc. In particular, they can contain 0.8-3 mg indapamide and 3-12 mg THPT or one of its pharmaceutically acceptable addition salts, as well as the auxiliaries or carriers customary for oral administration forms, and they can be administered in one or two daily doses.
8302435 v· - 5 - VOORBEELD: Tablet van 90 mg8302435 v - - 5 - EXAMPLE: 90 mg tablet
Indapamide 1,25 mg 8-(3-tert-butylamino-2-hydroxypropoxy)thiachroman-hydrochloride 5,00 mg 5 stearinezuur 0,90 mg natriumcarboxymethylzetmeel 3,00 mg microkristallijne cellulose 33,38 mg lactose 35,75 mg calciumwaterstoffosfaat 10,00 mg 10 colloidaal silica 0,27 mg magnesiumstearaat 0,45 mgIndapamide 1.25 mg 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman hydrochloride 5.00 mg 5 stearic acid 0.90 mg sodium carboxymethyl starch 3.00 mg microcrystalline cellulose 33.38 mg lactose 35.75 mg calcium hydrogen phosphate 10, 00 mg 10 colloidal silica 0.27 mg magnesium stearate 0.45 mg
Dit tablet kan bekleed worden.This tablet can be coated.
t 8302435t 8302435
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8212058 | 1982-07-09 | ||
| FR8212058A FR2529785A1 (en) | 1982-07-09 | 1982-07-09 | PHARMACEUTICAL COMPOSITION BASED ON INDAPAMIDE AND 8- (3-TERTBUTYLAMINO 2-HYDROXYPROPOXY) THIACHROMAN |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8302435A true NL8302435A (en) | 1984-02-01 |
Family
ID=9275835
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8302435A NL8302435A (en) | 1982-07-09 | 1983-07-08 | SYNERGISTIC ANTIHYPERTENSIVE PHARMACEUTICAL COMPOSITION. |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5927813A (en) |
| AU (1) | AU557601B2 (en) |
| BE (1) | BE897251A (en) |
| CA (1) | CA1197191A (en) |
| CH (1) | CH655007A5 (en) |
| DE (1) | DE3324785C2 (en) |
| FR (1) | FR2529785A1 (en) |
| GB (1) | GB2123293B (en) |
| IE (1) | IE55364B1 (en) |
| IT (1) | IT1173729B (en) |
| LU (1) | LU84902A1 (en) |
| NL (1) | NL8302435A (en) |
| NZ (1) | NZ204849A (en) |
| OA (1) | OA07489A (en) |
| SE (1) | SE8303886L (en) |
| ZA (1) | ZA834978B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8600137A (en) * | 1985-02-05 | 1986-09-01 | Sandoz Ag | PHARMACEUTICAL PREPARATIONS CONTAINING, WHEN DESIRED, COMBINED WITH 3-AMINOPROPOXYINDOLS DIURETICALLY AND METHODS FOR USING THESE PREPARATIONS. |
| PL193976B1 (en) * | 2002-07-01 | 2007-04-30 | Pliva Krakow | Prolonged effect containing indapamide and method of manufacture of prolonged effect tablets containing indapamide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1203691A (en) * | 1968-03-06 | 1970-09-03 | Science Union & Cie | New disubstituted n-amino indoline derivatives and process for preparing them |
| GB1308191A (en) * | 1970-04-06 | 1973-02-21 | Science Union & Cie | Thiochroman derivatives and a process for preparing them |
| IL39625A0 (en) * | 1971-06-15 | 1972-11-28 | Ciba Geigy Ag | New pharmaceutical preparations for the treatment of hypertonia,containing a diuretic and a beta-receptor blocking agent |
-
1982
- 1982-07-09 FR FR8212058A patent/FR2529785A1/en active Granted
-
1983
- 1983-07-06 LU LU84902A patent/LU84902A1/en unknown
- 1983-07-07 ZA ZA834978A patent/ZA834978B/en unknown
- 1983-07-07 IT IT48641/83A patent/IT1173729B/en active
- 1983-07-07 SE SE8303886A patent/SE8303886L/en not_active Application Discontinuation
- 1983-07-08 IE IE1597/83A patent/IE55364B1/en unknown
- 1983-07-08 NZ NZ204849A patent/NZ204849A/en unknown
- 1983-07-08 CA CA000432068A patent/CA1197191A/en not_active Expired
- 1983-07-08 OA OA58056A patent/OA07489A/en unknown
- 1983-07-08 DE DE3324785A patent/DE3324785C2/en not_active Expired
- 1983-07-08 BE BE0/211143A patent/BE897251A/en not_active IP Right Cessation
- 1983-07-08 CH CH3786/83A patent/CH655007A5/en not_active IP Right Cessation
- 1983-07-08 JP JP58124582A patent/JPS5927813A/en active Granted
- 1983-07-08 GB GB08318512A patent/GB2123293B/en not_active Expired
- 1983-07-08 NL NL8302435A patent/NL8302435A/en not_active Application Discontinuation
- 1983-07-08 AU AU16702/83A patent/AU557601B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5927813A (en) | 1984-02-14 |
| JPH0250084B2 (en) | 1990-11-01 |
| SE8303886L (en) | 1984-01-10 |
| GB2123293B (en) | 1985-10-09 |
| FR2529785B1 (en) | 1984-12-07 |
| CA1197191A (en) | 1985-11-26 |
| SE8303886D0 (en) | 1983-07-07 |
| DE3324785A1 (en) | 1984-01-12 |
| DE3324785C2 (en) | 1986-10-09 |
| AU1670283A (en) | 1984-01-12 |
| OA07489A (en) | 1985-03-31 |
| FR2529785A1 (en) | 1984-01-13 |
| GB8318512D0 (en) | 1983-08-10 |
| IE831597L (en) | 1984-01-09 |
| CH655007A5 (en) | 1986-03-27 |
| GB2123293A (en) | 1984-02-01 |
| IE55364B1 (en) | 1990-08-29 |
| ZA834978B (en) | 1984-03-28 |
| AU557601B2 (en) | 1986-12-24 |
| IT8348641A0 (en) | 1983-07-07 |
| BE897251A (en) | 1984-01-09 |
| IT1173729B (en) | 1987-06-24 |
| LU84902A1 (en) | 1984-03-22 |
| NZ204849A (en) | 1986-04-11 |
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