EP0822820A1 - NOVEL USE OF (S)-ADENOSYL-L-METHIONINE (SAMe) - Google Patents

NOVEL USE OF (S)-ADENOSYL-L-METHIONINE (SAMe)

Info

Publication number
EP0822820A1
EP0822820A1 EP96913500A EP96913500A EP0822820A1 EP 0822820 A1 EP0822820 A1 EP 0822820A1 EP 96913500 A EP96913500 A EP 96913500A EP 96913500 A EP96913500 A EP 96913500A EP 0822820 A1 EP0822820 A1 EP 0822820A1
Authority
EP
European Patent Office
Prior art keywords
same
patient
day
methionine
doses
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Withdrawn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
EP96913500A
Other languages
German (de)
French (fr)
Inventor
Georg Nemeth
Carlo Di Padova
Laszlo Szabo
Gerhard Gross
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.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
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 Knoll GmbH filed Critical Knoll GmbH
Publication of EP0822820A1 publication Critical patent/EP0822820A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • SAMe (S) -Adenosyl-L-methionine (SAMe) and its salts are already known, cf. EP-PS 162.323. It is also described that SAMe has a principal anti-ischemic effect (Eur. J. Pharmacol. 144: 211, 1987; Jpn. J. Pharmacol. 46: 225, 1988; Eur. J. Pharmacol. 166: 231, 1989; Jpn J. Pharmacol. 52: 141, 195 * 0). According to JP-PS 1,686,947, SAMe can be used for various indications relating to central damage. Daily doses of 100 mg to 1550 mg are given in this publication.
  • J. Pharmacol. 49, 119-124 (1989) describes the effect of SAMe on the Ca content and glucose metabolism and on mortality in rats after transient ischemia at doses of 100 mg / kg.
  • Acute embolic ischemia e.g. cardiac embolism, fatty
  • Thrombotic ischemia which includes the so-called cerebral
  • Ischemia Ischemias triggered by immunological, inflammatory mechanisms. This also includes focal ischemia caused by hemostasiological and immunological system diseases - focal ischemia, which are associated with special forms of vascular processes and other unusual causes. Traumatic brain and spinal injuries that lead directly or indirectly to focal ischemia (such as bulky intracerebral, subdural, ⁇ pidural ⁇ 'bleeding, brain contusions and laceration).
  • 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 provided or recommended for the above-mentioned indication in an amount of at least 2000 mg / day / patient, in particular at least 3000 mg / day / patient and preferably in doses of at least 7000 mg / day / patient.
  • the indication of the high dose according to the invention is an essential lesson in the obvious preparation of the drug.
  • SAMe is administered parenterally (intravenously, intraarterially or intramuscularly) in a customary manner, with intravenous administration being the preferred form of administration.
  • the above amount can be infused into the patient over a period of 1 to 24 hours for several days.
  • Application forms which contain 6-18% by weight of SAMe together with lysine in water are particularly suitable for the use according to the invention.
  • Such an application form can, for example, be the following Composition: 400 mg SAMe, 324.3 mg L-lysine, 11.5 mg NaOH and 472.1 mg water for injections.

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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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The use of SAMe and its physiologically acceptable salts in doses of over 2000 mg per day and patient for the parenteral treatment of conditions triggered by focal permanent ischaemia.

Description

Neue Verwendung von (S)-Adenosyl-L-methionin (SAMe)New use of (S) -denosyl-L-methionine (SAMe)
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. Pharmacol. 144: 211, 1987; Jpn. J. Pharmacol. 46: 225, 1988; Eur. J. Pharmacol. 166: 231, 1989; Jpn. J. Pharmacol. 52: 141, 195*0) . Gemäß JP-PS 1.686.947 läßt sich SAMe bei verschiedenen Indikationen einsetzen, die sich auf zentrale Schädigungen beziehen. In dieser Druckschrift werden tägliche Dosen von 100 mg bis 1550 mg angegeben.(S) -Adenosyl-L-methionine (SAMe) and its salts are already known, cf. EP-PS 162.323. It is also described that SAMe has a principal anti-ischemic effect (Eur. J. Pharmacol. 144: 211, 1987; Jpn. J. Pharmacol. 46: 225, 1988; Eur. J. Pharmacol. 166: 231, 1989; Jpn J. Pharmacol. 52: 141, 195 * 0). According to JP-PS 1,686,947, SAMe can be used for various indications relating to central damage. Daily doses of 100 mg to 1550 mg are given in this publication.
Aus Atti e Memorie della Societa Medica del Lazio, Anno I, Nr. 3, 1983, 1-14, ist es bekannt, Patienten mit Nierenversagen mit SAMe-Dosen von 3 bzw. 5 g/Tag zu behandeln.From Atti e Memorie della Societa Medica del Lazio, Anno I, No. 3, 1983, 1-14, it is known to treat patients with kidney failure with SAMe doses of 3 or 5 g / day.
In Japan, J. Pharmacol. 49, 119-124 (1989) wird die Wirkung von SAMe auf den Ca-Gehalt und Glukosemetabolismus sowie auf die Mortalität in Ratten nach einer vorrübergehenden Ischämie bei Dosierungen von 100 mg/kg beschrieben.In Japan, J. Pharmacol. 49, 119-124 (1989) describes the effect of SAMe on the Ca content and glucose metabolism and on mortality in rats after transient ischemia at doses of 100 mg / kg.
Die antiischämische Wirkung von SAMe wurde jedoch nur bei der Behandlung der globalen und transienten 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 z.B. 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 and transient 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 is not transferable to other ischemic diseases of the brain, especially not to focal ischemia, e.g. caused by the occlusion of an intracranial vessel (Cerebrovasc. Brain Metab. Rev. 2: 1, 1990).
Die wichtigsten Pathogenesen der fokalen Ischämie, bei denen Schädigungen bis zum letalen Ausgang auftreten können, sind folgende:The main pathogenesis of focal ischemia, in which damage can occur up to the lethal outcome, are as follows:
Akute embolische Ischämien, z.B. kardiale Embolie, Fett-,Acute embolic ischemia, e.g. cardiac embolism, fatty,
LuftembolienAir embolism
Thrombotische Ischämien, dazu gehören die sog. zerebralenThrombotic ischemia, which includes the so-called cerebral
Mikro- und Makroangiopathien - Hämodynamisch d.h. z.B. fokale durch Vasospasmen verursachteMicro- and Macroangiopathies - Hemodynamic i.e. e.g. focal caused by vasospasm
Ischämien Durch immunologische, entzündliche Mechanismen ausgelöste Ischämien. Hierzu gehören auch die durch hämostasiologische und immunologische Systemerkrankungen hervorgerufene fokalen Ischämien - Fokale Ischämien, die mit Sonderformen der Gefäßprozesse und anderen ungewöhnlichen Ursachen in Zusammenhang stehen. Traumatische Hirn- und Rückenmar schaden, die direkter- oder indirekterweise zu fokalen Ischämien führen (wie z.B. raumfordernde intrazerebrale, subdurale, βpiduralβ' Blutungen, Hirnkontusionen und Lazerationen) .Ischemia Ischemias triggered by immunological, inflammatory mechanisms. This also includes focal ischemia caused by hemostasiological and immunological system diseases - focal ischemia, which are associated with special forms of vascular processes and other unusual causes. Traumatic brain and spinal injuries that lead directly or indirectly to focal ischemia (such as bulky intracerebral, subdural, βpiduralβ 'bleeding, brain contusions and laceration).
Gegenstand der vorliegenden Erfindung ist die Verwendung von SAMe und dessen physiologisch verträglichen Salzen in Dosen von mindestens 2000 mg/Tag/Patient zur parenteralen Behandlung von Schädigungen, die durch fokale permanente Ischämie ausgelöst werden.The present invention relates to the use of SAMe and its physiologically tolerable salts in doses of at least 2000 mg / day / patient for the parenteral treatment of damage caused by focal permanent 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 die oben genannte Indikation in einer Menge von mindestens 2000 mg/Tag/Patient, insbesondere von mindestens 3000 mg/Tag/Patient und bevorzugt in Dosen von mindestens 7000 mg/Tag/Patient vorgesehen bzw. empfohlen. Die Angabe der hohen erfindungsgemäßen Dosis ist eine wesentliche Lehre bei der augenfälligen Herrichtung des Arzneimittels.SAMe or its salts are provided or recommended for the above-mentioned indication in an amount of at least 2000 mg / day / patient, in particular at least 3000 mg / day / patient and preferably in doses of at least 7000 mg / day / patient. The indication of the high dose according to the invention is an essential lesson in the obvious preparation of the drug.
SAMe wird in üblicher Weise parenteral (intravenös, intraarteriell oder intramuskulär) verabreicht, wobei die intravenöse Verabreichung die bevorzugte Applikationsform darstellt. Die oben angegebene Menge kann dem Patienten über einen Zeitraum von 1 bis 24 Stunden mehrere Tage lang infundiert werden.SAMe is administered parenterally (intravenously, intraarterially or intramuscularly) in a customary manner, with intravenous administration being the preferred form of administration. The above amount can be infused into the patient over a period of 1 to 24 hours for several days.
SAMe bzw. dessen Salze kann in den gebräuchlichen galenischen Applikationsformen flüssig angewendet werden, z. B. als Lösung. Die Applikationsformen enthalten den Wirkstoff normalerweise in einer Menge von 1 bis 50 %, vorzugsweise 5 bis 20 %.SAMe or its salts can be used in the usual galenical application forms, e.g. B. as a solution. The administration forms normally contain the active ingredient in an amount of 1 to 50%, preferably 5 to 20%.
Für die erfindungsgemäße Verwendung besonders geeignet sind Applikationsformen, die 6-18 Gew.-% SAMe zusammen mit Lysin in Wasser enthalten. Eine solche Applikationsform kann z.B. folgende Zusammensetzung haben: 400 mg SAMe, 324,3 mg L-Lysin, 11,5 mg NaOH und 472,1 mg Wasser für Injektionen.Application forms which contain 6-18% by weight of SAMe together with lysine in water are particularly suitable for the use according to the invention. Such an application form can, for example, be the following Composition: 400 mg SAMe, 324.3 mg L-lysine, 11.5 mg NaOH and 472.1 mg water for injections.
Überraschend hat sich gezeigt, daß bei der Verwendung von SAMe im Dosisbereich von mehr als 2000 mg bei der Behandlung von fokalen Ischämien im Vergleich zu anderen Therapien, eine mortalitätsinkende Wirkung auftritt.Surprisingly, it has been shown that when using SAMe in the dose range of more than 2000 mg in the treatment of focal ischemia in comparison to other therapies, a mortality-reducing effect occurs.
Die die Sterblichkeit herabsetzende Wirkung von SAMe bei Schädigungen durch fokale Ischämie zeigt die folgende klinische Untersuchung am Beispiel des Gehirns:The following clinical examination using the example of the brain shows that SAMe has a mortality-reducing effect on focal ischemia damage:
An Schlaganfallpatienten wurden unter Doppelblindbedingungen zwei placebokontrollierte Studien durchgeführt . Patienten in der Verumgruppe wurden 14 Tage lang mit 2400 oder 3200 mg pro Tag SAMe intravenös behandel . Unter diesen Bedingungen traten keine nennenswerten Nebenwirkungen auf. Wie der Tabelle 1 zu entnehmen ist, führte die Behandlung mit SAMe zu signifikant niedrigerer Mortalität in beiden Verumgruppen als in der Placebogruppe. Eine Besonderheit der Studie ist, daß die Patienten in der Regel zwischen 12-24 Stunden nach dem ischämischen Insult angefangen wurden zu behandeln, d.h. daß mehrere Stunden nach dem Auftritt der Durchblutungsstörungen die klinische Wirkung immer noch nachweisbar ist.Two placebo-controlled studies were carried out on stroke patients under double-blind conditions. Patients in the verum group were treated with SAMe at 2400 or 3200 mg per day for 14 days. No significant side effects occurred under these conditions. As can be seen in Table 1, treatment with SAMe resulted in significantly lower mortality in both verum groups than in the placebo group. A peculiarity of the study is that the patients usually started treatment between 12-24 hours after the ischemic insult, i.e. that the clinical effect is still demonstrable several hours after the appearance of circulatory disorders.
Tabelle 1Table 1
Anzahl der verstorbenen Placebo: 5 von 14 Patienten PatientenNumber of deceased placebo: 5 patients out of 14 patients
2400 mg SAMe: 1 von 14 Patienten2400 mg SAMe: 1 in 14 patients
3200 mg SAMe: 0 von 14 Patienten 3200 mg SAMe: 0 out of 14 patients

Claims

Patentansprüche claims
1. Verwendung von (S)-Adenosyl-L-methionin (SAMe) und dessen physiologisch verträglichen Salzen in Dosen von mindestens 2000 mg/Tag/Patient zur parenteralen Behandlung von Schädi¬ gungen, die durch fokale permanente Ischämie ausgelöst wer¬ den.1. Use of (S) -denosyl-L-methionine (SAMe) and its physiologically tolerable salts in doses of at least 2000 mg / day / patient for the parenteral treatment of injuries which are triggered by focal permanent ischemia.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß SAMe oder dessen physiologisch verträgliche Salze in Dosen von mindestens 3000 mg/Tag/Patient vorgesehen werden.2. Use according to claim 1, characterized in that SAMe or its physiologically tolerable salts are provided in doses of at least 3000 mg / day / patient.
3. Verwendung von (S) -Andenosyl-L-methionin und dessen physiolo- gisch verträglichen Salzen zur Herstellung eines Arzneimit¬ tels, das in Dosen von mindestens 2000 mg/Tag/Patient vorge¬ sehen wird, zur parenteralen Behandlung von Schädigungen, die durch fokale permanente Ischämie ausgelöst werden.3. Use of (S) -Andenosyl-L-methionine and its physiologically tolerable salts for the production of a medicament which is provided in doses of at least 2000 mg / day / patient for the parenteral treatment of damage which caused by focal permanent ischemia.
4. Methode zur Behandlung von Patienten, die an Schädigungen leiden, die durch fokale permanente Ischämie ausgelöst wer¬ den, dadurch gekennzeichnet, daß man diesen mindestens 2000 mg/Tag/Patient an (S)-Adenosyl-L-methionen (SAME) verab¬ reicht. 4. Method for the treatment of patients suffering from damage caused by focal permanent ischemia, characterized in that it is administered to at least 2000 mg / day / patient of (S) -adenosyl-L-methion (SAME) ¬ is enough.
Neue Verwendung von (S)-Adenosyl-L-methionin (SAMe)New use of (S) -denosyl-L-methionine (SAMe)
ZusammenfassungSummary
Verwendung von SAMe und dessen physiologisch verträglichen Salzen in Dosen von über 2000 mg pro Tag und Patient zur parenteralen Behandlung von Schädigungen, die durch fokale permanente Ischämie ausgelöst werden. Use of SAMe and its physiologically acceptable salts in doses of over 2000 mg per day and patient for the parenteral treatment of damage caused by focal permanent ischemia.
EP96913500A 1995-04-26 1996-04-13 NOVEL USE OF (S)-ADENOSYL-L-METHIONINE (SAMe) Withdrawn EP0822820A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19515275A DE19515275A1 (en) 1995-04-26 1995-04-26 New use of (S) -denosyl-L-methionine (SAMe)
DE19515275 1995-04-26
PCT/EP1996/001570 WO1996033727A1 (en) 1995-04-26 1996-04-13 NOVEL USE OF (S)-ADENOSYL-L-METHIONINE (SAMe)

Publications (1)

Publication Number Publication Date
EP0822820A1 true EP0822820A1 (en) 1998-02-11

Family

ID=7760373

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96913500A Withdrawn EP0822820A1 (en) 1995-04-26 1996-04-13 NOVEL USE OF (S)-ADENOSYL-L-METHIONINE (SAMe)

Country Status (15)

Country Link
EP (1) EP0822820A1 (en)
JP (1) JPH11504023A (en)
KR (1) KR19990008061A (en)
CN (1) CN1182367A (en)
AR (1) AR001687A1 (en)
AU (1) AU5646396A (en)
CA (1) CA2216854A1 (en)
CZ (1) CZ330597A3 (en)
DE (1) DE19515275A1 (en)
HR (1) HRP960196A2 (en)
IL (1) IL117844A0 (en)
MX (1) MX9707735A (en)
NO (1) NO974941D0 (en)
WO (1) WO1996033727A1 (en)
ZA (1) ZA963296B (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE37913B1 (en) * 1972-08-02 1977-11-09 Bioresearch Sas Salt of s-adenosyl-l-methionine
JPS59139319A (en) * 1983-01-31 1984-08-10 Fuji Kagaku Kogyo Kk Remedy for body dysfunction caused by cerebral disorder
JPH02290896A (en) * 1989-04-28 1990-11-30 Fuji Kagaku Kogyo Kk Novel s-adenosylmethionine derivative
DE4425280C2 (en) * 1994-07-16 1997-05-07 Knoll Ag Use of (S) -denosyl-L-methionine and its physiologically tolerable salts for the treatment of reperfusion damage that is triggered after temporary focal ischemia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9633727A1 *

Also Published As

Publication number Publication date
KR19990008061A (en) 1999-01-25
MX9707735A (en) 1997-12-31
DE19515275A1 (en) 1996-10-31
HRP960196A2 (en) 1998-02-28
CN1182367A (en) 1998-05-20
IL117844A0 (en) 1996-08-04
CZ330597A3 (en) 1998-02-18
ZA963296B (en) 1997-10-27
NO974941L (en) 1997-10-24
CA2216854A1 (en) 1996-10-13
NO974941D0 (en) 1997-10-24
JPH11504023A (en) 1999-04-06
WO1996033727A1 (en) 1996-10-31
AU5646396A (en) 1996-11-18
AR001687A1 (en) 1997-11-26

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