EP0771202A1 - USE OF (S)-ADENOSYL-L-METHIONINE (SAMe) AND ITS PHYSIOLOGICALLY COMPATIBLE SALTS FOR TREATING REPERFUSION DAMAGE TRIGGERED BY TEMPORARY FOCAL ISCHAEMIA - Google Patents
USE OF (S)-ADENOSYL-L-METHIONINE (SAMe) AND ITS PHYSIOLOGICALLY COMPATIBLE SALTS FOR TREATING REPERFUSION DAMAGE TRIGGERED BY TEMPORARY FOCAL ISCHAEMIAInfo
- Publication number
- EP0771202A1 EP0771202A1 EP95924974A EP95924974A EP0771202A1 EP 0771202 A1 EP0771202 A1 EP 0771202A1 EP 95924974 A EP95924974 A EP 95924974A EP 95924974 A EP95924974 A EP 95924974A EP 0771202 A1 EP0771202 A1 EP 0771202A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- same
- methionine
- reperfusion damage
- adenosyl
- physiologically compatible
- 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- Withdrawn
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- SAMe -Adenosyl-L-methionine
- SAMe can be used for various indications relating to central damage.
- the main manifestations of temporary focal ischemia are the following: (1) acute thromboembolic ischemia, where reperfusion by administration of thrombolytically active substances (such as urokinase, streptokinase or t-PA) or by surgery Measures are initiated, (2) vasospasms that dissolve spontaneously or after administration of vasodilatory substances, (3) surgical interventions, in which the temporary occlusion of an artery is initiated for operational reasons, and (4) transient ischemic attacks with unexplained
- the present invention relates to the use of SAMe and its physiologically tolerable salts for the treatment of reperfusion damage which is triggered by temporary focal ischemia.
- SAMe is preferably used in the form of a salt with a physiologically acceptable acid.
- Preferred acids are: hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and butanedisulfonic acid.
- SAMe or its salts are administered for these indications in an amount of 10 to 1000 mg / kg body weight.
- SAMe can be administered parenterally (intravenously, intraarterially or intramuscularly) in a customary manner, with intravenous infusion being the preferred form of administration.
- the above amount is usually infused into the patient once over a period of 1 to 24 hours.
- SAMe can be applied in the usual galeni Customer application forms liquid, z. B. as a solution.
- the application forms normally contain the active ingredient in an amount of 1 to 50%, preferably 5 to 20%.
- the effect of SAMe on the size of the cerebral infarction caused by temporary focal cerebral ischemia was determined in the rat using the modified method of Chen et al. (Stroke 17: 738, 1986). For this, the right-sided A. cerebri media and the two Aa. carotis sess under halothane anesthesia exposed and occluded for 90 min. The size of the cerebral infarction was determined 24 hours later after staining with triphenyltetrazolium chloride.
- test animals were treated with 40 mg / kg + 100 mg / kg / h SAMe intravenously.
- the bolus was given either at the end of the 90-minute occlusion or 30 minutes later; the continuous infusion was maintained for 6 hours.
- Table 1 the temporary vascular occlusion resulted in significantly smaller cerebral infarcts when treated with SAMe than when treated with placebo (0.9% NaCl solution).
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Verwendung von (S)-Adenosyl-L-methionin (SAMe) und dessen physiologisch verträglichen Salzen zur Behandlung von Reperfusionsschaden, die durch temporäre fokale Ischämie ausgelöst werdenUse of (S) -Adenosyl-L-methionine (SAMe) and its physiologically tolerable salts for the treatment of reperfusion damage caused by temporary focal ischemia
Beschreibungdescription
(S)-Adenosyl-L-methionin (SAMe) und dessen Salze sind bereits bekannt, vgl. EP-PS 162.323. Es ist auch beschrieben, daß SAMe eine prinzipielle antiischämische Wirkung besitzt (Eur. J.(S) -Adenosyl-L-methionine (SAMe) and its salts are already known, cf. EP-PS 162.323. It is also described that SAMe has a basic anti-ischemic effect (Eur. J.
Phar acol. 144: 211, 1987; Jpn. J. Pharmacol. 46: 225, 1988; Eur.Phar acol. 144: 211, 1987; Jpn. J. Pharmacol. 46: 225, 1988; Eur.
J. Pharmacol. 166: 231, 1989; Jpn. J. Pharmacol. 52: 141, 1990).J. Pharmacol. 166: 231, 1989; Jpn. J. Pharmacol. 52: 141, 1990).
Gemäß JP-PS 8.312.642 läßt sich SAMe bei verschiedenen Indikationen einsetzen, die sich auf zentrale Schädigungen beziehen.According to JP-PS 8.312.642, SAMe can be used for various indications relating to central damage.
Die antiischämische Wirkung von SAMe wurde jedoch nur bei der Behandlung der globalen zerebralen Ischämie gezeigt. Einer globalen zerebralen Ischämie liegt der vollständige Ausfall der zerebralen Blutversorgung zugrunde, wie er beispielsweise während eines Herzstillstandes auftritt. Es ist bekannt, daß die therapeutische Wirkung einer Substanz bei globaler Ischämie auf andersartige ischämische Erkrankungen des Gehirns nicht übertragbar ist, insbesondere nicht auf fokale Ischämien, die durch den Verschluß eines intrakraniellen Gefäßes hervorgerufen werden (Cerebrovasc. Brain Metab. Rev. 2: 1, 1990).However, the anti-ischemic effect of SAMe has only been shown in the treatment of global cerebral ischemia. Global cerebral ischemia is based on the complete failure of the cerebral blood supply, such as occurs during cardiac arrest. It is known that the therapeutic effect of a substance in global ischemia cannot be transferred to other ischemic diseases of the brain, in particular not to focal ischemia caused by the occlusion of an intracranial vessel (Cerebrovasc. Brain Metab. Rev. 2: 1, 1990).
Es ist weiterhin bekannt, daß bei der temporären fokalen Ischämie die Wiederherstellung der Blutversorgung sekundäre biochemische Prozesse auslöst, die zu sogenannten Reperfusionsschäden führen (Arch. Neurol. 47: 1245, 1990). Es wird angenommen, daß die Reperfusionsschäden in erster Linie durch freie Sauerstoff¬ radikale (Superoxid und Hydroxylradikal) vermittelt werden (Neurosurgery 27: 1, 1990). Obwohl die Reperfusion für dieIt is also known that in the case of temporary focal ischemia, the restoration of the blood supply triggers secondary biochemical processes which lead to so-called reperfusion damage (Arch. Neurol. 47: 1245, 1990). It is believed that the reperfusion damage is mediated primarily by free oxygen radicals (superoxide and hydroxyl radical) (Neurosurgery 27: 1, 1990). Although the reperfusion for the
Verhinderung von irreversiblen Schäden unerläßlich ist, bewirkt sie ihrerseits Reperfusionsschäden. Daher kann das Ausmaß von Gewebsschaden durch Pharmaka weiter reduziert werden, wenn diese die Reperfusionsschäden minimieren oder verhindern. Diese Prozesse sind sowohl am Gehirn als auch am Herzen (Annu. Rev. Physiol. 52: 487, 1990) nachgewiesen worden.Prevention of irreversible damage is essential, it in turn causes reperfusion damage. Therefore, the extent of tissue damage from drugs can be further reduced if they minimize or prevent reperfusion damage. These processes have been demonstrated in both the brain and the heart (Annu. Rev. Physiol. 52: 487, 1990).
Die wichtigsten Erscheinungsformen der temporären fokalen Ischämie, bei denen derartige sekundäre Schäden auftreten können, sind folgende: (1) akute thromboembolische Ischämien, wo die Reperfusion durch Gabe von thrombolytisch wirksamen Substanzen (wie Urokinase, Streptokinase oder t-PA) oder durch operative Maßnahmen eingeleitet wird, (2) Vasospasmen, die sich spontan oder nach Gabe von vasodilatorisch wirksamen Substanzen auflösen, (3) chirurgische Eingriffe, bei denen der temporäre Verschluß einer Arterie aus operationstechnischen Gründen eingeleitet wird, und (4) transiente ischämische Attacken mit ungeklärterThe main manifestations of temporary focal ischemia, in which such secondary damage can occur, are the following: (1) acute thromboembolic ischemia, where reperfusion by administration of thrombolytically active substances (such as urokinase, streptokinase or t-PA) or by surgery Measures are initiated, (2) vasospasms that dissolve spontaneously or after administration of vasodilatory substances, (3) surgical interventions, in which the temporary occlusion of an artery is initiated for operational reasons, and (4) transient ischemic attacks with unexplained
Ätiologie. Es existiert zur Zeit keine anerkannte Therapie für die Behandlung von Reperfusionsschäden, die als Begleit¬ erscheinung einer temporären fokalen Ischämie auftreten.Etiology. There is currently no recognized therapy for the treatment of reperfusion damage that occurs as a concomitant phenomenon of temporary focal ischemia.
Gegenstand der vorliegenden Erfindung ist die Verwendung von SAMe und dessen physiologisch verträglichen Salzen zur Behandlung von Reperfusionsschäden, die durch temporäre fokale Ischämie ausgelöst werden.The present invention relates to the use of SAMe and its physiologically tolerable salts for the treatment of reperfusion damage which is triggered by temporary focal ischemia.
SAMe wird vorzugsweise in Form eines Salzes mit einer physiologisch verträglichen Säure eingesetzt. Bevorzugte Säuren sind: Salzsäure, Schwefelsäure, Phosphorsäure, Ameisensäure, Essigsäure, Zitronensäure, Weinsäure, Methansulfonsäure, p-Toluolsulfonsäure und Butandisulfonsäure.SAMe is preferably used in the form of a salt with a physiologically acceptable acid. Preferred acids are: hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and butanedisulfonic acid.
SAMe bzw. dessen Salze werden für diese Indikationen in einer Menge von 10 bis 1000 mg/kg Körpergewicht verabfolgt.SAMe or its salts are administered for these indications in an amount of 10 to 1000 mg / kg body weight.
SAMe kann in üblicher Weise parenteral (intravenös, intraarteriell oder intramuskulär) verabfolgt werden, wobei die intravenöse Infusion die bevorzugte Applikationsform darstellt. Die oben angegebene Menge wird dem Patienten in der Regel einmal über einen Zeitraum von 1 bis 24 Stunden infundiert.SAMe can be administered parenterally (intravenously, intraarterially or intramuscularly) in a customary manner, with intravenous infusion being the preferred form of administration. The above amount is usually infused into the patient once over a period of 1 to 24 hours.
SAMe kann in den gebräuchlichen galenisehen Applikationsformen flüssig angewendet werden, z. B. als Lösung. Die Applikations¬ formen enthalten den Wirkstoff normalerweise in einer Menge von 1 bis 50 %, vorzugsweise 5 bis 20 %.SAMe can be applied in the usual galenisehen application forms liquid, z. B. as a solution. The application forms normally contain the active ingredient in an amount of 1 to 50%, preferably 5 to 20%.
Der besondere Vorteil bei der Verwendung von SAMe im Vergleich zu anderen Therapien besteht darin, daß die Behandlung mit SAMe auch dann eine hervorragende protektive Wirkung zeigt, wenn sie erst in der Reperfusionsphase initiiert wird.The particular advantage of using SAMe compared to other therapies is that treatment with SAMe shows an excellent protective effect even if it is only initiated in the reperfusion phase.
Die Wirksamkeit von SAMe gegen Reperfusionsschäden zeigt der folgende Versuch am Beispiel des Gehirns:The following experiment shows the effectiveness of SAMe against reperfusion damage using the example of the brain:
Die Wirkung von SAMe auf die Größe des durch temporäre fokale zerebrale Ischämie ausgelösten Hirninfarktes wurde an der Ratte nach der modifizierten Methode von Chen et al. (Stroke 17: 738, 1986) untersucht. Dazu wurden die rechtsseitige A. cerebri media und die beiden Aa. carotis communes unter Halothannarkose freigelegt und 90 min lang okkludiert. Die Größe des Hirninfarktes wurde 24 h später nach Färbung mit Triphenyltetrazoliumchlorid quantitativ ermittelt.The effect of SAMe on the size of the cerebral infarction caused by temporary focal cerebral ischemia was determined in the rat using the modified method of Chen et al. (Stroke 17: 738, 1986). For this, the right-sided A. cerebri media and the two Aa. carotis communes under halothane anesthesia exposed and occluded for 90 min. The size of the cerebral infarction was determined 24 hours later after staining with triphenyltetrazolium chloride.
In der Substanzgruppe wurden die Versuchstiere mit 40 mg/kg + 100 mg/kg/h SAMe intravenös behandelt. Die Bolusgabe erfolgte entweder am Ende der 90minütigen Okklusion oder 30 min später; die Dauerinfusion wurde 6 h lang aufrechterhalten. Wie der Tabelle 1 zu entnehmen ist, führte die temporäre Gefäßokklusion bei Behandlung mit SAMe zu signifikant kleineren zerebralen Infarkten als bei Placebo-Behandlung (0.9 % NaCl-Lösung) .In the substance group, the test animals were treated with 40 mg / kg + 100 mg / kg / h SAMe intravenously. The bolus was given either at the end of the 90-minute occlusion or 30 minutes later; the continuous infusion was maintained for 6 hours. As can be seen from Table 1, the temporary vascular occlusion resulted in significantly smaller cerebral infarcts when treated with SAMe than when treated with placebo (0.9% NaCl solution).
Diese Befunde machen die spezifische Wirkung von SAMe auf die Reperfusionsprozesse deutlich: Obwohl die Therapie mit SAMe erst in der postischämischen Reperfusionsphase initiiert wurde, bewirkte sie eine signifikante Verringerung des entstehenden Hirninfarktes.These findings clearly show the specific effect of SAMe on the reperfusion processes: Although the therapy with SAMe was only initiated in the post-ischemic reperfusion phase, it caused a significant reduction in the brain infarction that occurred.
Tabelle 1Table 1
Postischämische Latenz, min 0 30Post-ischemic latency, min 0 30
Infarktvolumen Placebo 100 ± 6 [7] 100 ± 8 [11] in % derInfarct volume placebo 100 ± 6 [7] 100 ± 8 [11] in% of
Kontrollecontrol
(Mittelwert ± Standardfehler SAMe 57 ± 6 [8] 66 ± 8 [10](Mean ± standard error SAMe 57 ± 6 [8] 66 ± 8 [10]
[Zahl der[Number of
Versuche] ) p (zweiseitiger < 0.001 < 0.01 t-Test) Tests]) p (two-sided <0.001 <0.01 t test)
Claims
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4425280 | 1994-07-16 | ||
| DE4425280A DE4425280C2 (en) | 1994-07-16 | 1994-07-16 | Use of (S) -denosyl-L-methionine and its physiologically tolerable salts for the treatment of reperfusion damage that is triggered after temporary focal ischemia |
| PCT/EP1995/002598 WO1996002252A1 (en) | 1994-07-16 | 1995-07-05 | USE OF (S)-ADENOSYL-L-METHIONINE (SAMe) AND ITS PHYSIOLOGICALLY COMPATIBLE SALTS FOR TREATING REPERFUSION DAMAGE TRIGGERED BY TEMPORARY FOCAL ISCHAEMIA |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0771202A1 true EP0771202A1 (en) | 1997-05-07 |
Family
ID=6523426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP95924974A Withdrawn EP0771202A1 (en) | 1994-07-16 | 1995-07-05 | USE OF (S)-ADENOSYL-L-METHIONINE (SAMe) AND ITS PHYSIOLOGICALLY COMPATIBLE SALTS FOR TREATING REPERFUSION DAMAGE TRIGGERED BY TEMPORARY FOCAL ISCHAEMIA |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5776911A (en) |
| EP (1) | EP0771202A1 (en) |
| JP (1) | JPH10502652A (en) |
| KR (1) | KR970704442A (en) |
| AU (1) | AU2927195A (en) |
| BG (1) | BG101145A (en) |
| CA (1) | CA2195345A1 (en) |
| CZ (1) | CZ12297A3 (en) |
| DE (1) | DE4425280C2 (en) |
| FI (1) | FI970165L (en) |
| HR (1) | HRP950405A2 (en) |
| HU (1) | HUT76834A (en) |
| IL (1) | IL114540A0 (en) |
| NO (1) | NO970185L (en) |
| PL (1) | PL318318A1 (en) |
| SI (1) | SI9520087A (en) |
| WO (1) | WO1996002252A1 (en) |
| ZA (1) | ZA955865B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19515275A1 (en) * | 1995-04-26 | 1996-10-31 | Knoll Ag | New use of (S) -denosyl-L-methionine (SAMe) |
| IT1317920B1 (en) * | 2000-10-20 | 2003-07-15 | Univ Roma | S-ADENOSYLMETHIONINE AND ITS DERIVATIVES FOR THE TREATMENT AND PREVENTION OF ALZHEIMER DISEASE. |
| US8841344B2 (en) | 2002-10-03 | 2014-09-23 | Hill's Pet Nutrition, Inc. | Method of using omega-3 fatty acids |
| FR2884421B1 (en) | 2005-04-15 | 2007-08-10 | Virbac Sa | NEW MEANS FOR CONTROLLING BEHAVIORAL DISORDERS IN PETS |
| WO2006111541A2 (en) * | 2005-04-20 | 2006-10-26 | Basf Plant Science Gmbh | Expression cassettes for seed-preferential expression in plants |
| CA2718469C (en) | 2008-03-17 | 2017-07-04 | National Research Council Of Canada | Aromatic prenyltransferase from hop |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1173990B (en) * | 1984-05-16 | 1987-06-24 | Bioresearch Spa | STABLE SALTS OF SULPHO-ADENOSYL-METHIONINE (SAME) PARTICULARLY SUITABLE FOR PARENTERAL USE |
| JPH0770235B2 (en) * | 1988-06-24 | 1995-07-31 | 株式会社東芝 | Non-volatile memory circuit device |
| JPH02290896A (en) * | 1989-04-28 | 1990-11-30 | Fuji Kagaku Kogyo Kk | Novel s-adenosylmethionine derivative |
-
1994
- 1994-07-16 DE DE4425280A patent/DE4425280C2/en not_active Expired - Fee Related
-
1995
- 1995-07-05 FI FI970165A patent/FI970165L/en not_active Application Discontinuation
- 1995-07-05 JP JP8504640A patent/JPH10502652A/en active Pending
- 1995-07-05 EP EP95924974A patent/EP0771202A1/en not_active Withdrawn
- 1995-07-05 WO PCT/EP1995/002598 patent/WO1996002252A1/en not_active Ceased
- 1995-07-05 AU AU29271/95A patent/AU2927195A/en not_active Abandoned
- 1995-07-05 PL PL95318318A patent/PL318318A1/en unknown
- 1995-07-05 US US08/776,006 patent/US5776911A/en not_active Expired - Lifetime
- 1995-07-05 SI SI9520087A patent/SI9520087A/en unknown
- 1995-07-05 CZ CZ97122A patent/CZ12297A3/en unknown
- 1995-07-05 CA CA002195345A patent/CA2195345A1/en not_active Abandoned
- 1995-07-05 KR KR1019970700288A patent/KR970704442A/en not_active Withdrawn
- 1995-07-05 HU HU9700130A patent/HUT76834A/en unknown
- 1995-07-11 IL IL11454095A patent/IL114540A0/en unknown
- 1995-07-14 HR HRP4425280.3A patent/HRP950405A2/en not_active Application Discontinuation
- 1995-07-14 ZA ZA955865A patent/ZA955865B/en unknown
-
1997
- 1997-01-15 NO NO970185A patent/NO970185L/en unknown
- 1997-01-17 BG BG101145A patent/BG101145A/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9602252A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FI970165A7 (en) | 1997-03-14 |
| US5776911A (en) | 1998-07-07 |
| DE4425280C2 (en) | 1997-05-07 |
| NO970185D0 (en) | 1997-01-15 |
| HRP950405A2 (en) | 1997-10-31 |
| PL318318A1 (en) | 1997-06-09 |
| NO970185L (en) | 1997-03-12 |
| ZA955865B (en) | 1997-01-14 |
| BG101145A (en) | 1997-08-29 |
| FI970165A0 (en) | 1997-01-15 |
| IL114540A0 (en) | 1995-11-27 |
| AU2927195A (en) | 1996-02-16 |
| CZ12297A3 (en) | 1998-04-15 |
| MX9700439A (en) | 1998-05-31 |
| FI970165L (en) | 1997-03-14 |
| DE4425280A1 (en) | 1996-01-18 |
| WO1996002252A1 (en) | 1996-02-01 |
| SI9520087A (en) | 1997-08-31 |
| HU9700130D0 (en) | 1997-02-28 |
| HUT76834A (en) | 1997-11-28 |
| KR970704442A (en) | 1997-09-06 |
| JPH10502652A (en) | 1998-03-10 |
| CA2195345A1 (en) | 1996-02-01 |
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