WO1998025607A1 - Use of inhibitors of monoamine oxidase type a for treating seizure disorders - Google Patents

Use of inhibitors of monoamine oxidase type a for treating seizure disorders Download PDF

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WO1998025607A1
WO1998025607A1 PCT/EP1997/006717 EP9706717W WO9825607A1 WO 1998025607 A1 WO1998025607 A1 WO 1998025607A1 EP 9706717 W EP9706717 W EP 9706717W WO 9825607 A1 WO9825607 A1 WO 9825607A1
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monoamine oxidase
type
inhibitors
reversible
esuprone
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PCT/EP1997/006717
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French (fr)
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Gerhard Gross
Hans-Jürgen Teschendorf
Wolfgang Löscher
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Knoll Aktiengesellschaft
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen

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  • the present invention relates to the use of reversible, selective inhibitors of type A monoamine oxidase for the treatment of epileptic diseases.
  • a typical example of a reversible, selective inhibitor of type A monoamine oxidase is ⁇ suprone, the ethanesulfonic acid ester of 7-hydroxy-3, 4-dimethyl-coumarin.
  • This substance is known as an active ingredient for the pharmacotherapy of mental disorders, in particular depression and allergic diseases (EP-OS 111 746, example 39).
  • Esuprone is characterized as a selective and reversible monoamine oxidase type A (MAO A) inhibitor.
  • MAO A monoamine oxidase type A
  • This monoamine oxidase is an enzyme that is responsible in the vertebrate organism for the inactivation of biogenic amines such as noradrenaline, dopa- in, serotonin and phenylethylamine.
  • Type A mainly affects the metabolism of noradrenaline, dopamine and serotonin.
  • Esuprone has an affinity for type A that is approx.
  • Esuprone The inhibition of MAO A by Esuprone is reversible [Traut et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 345, R124 (1992)], i.e. the connection between Esuprone and the enzyme necessary for enzyme inhibition can be removed (for example by the metabolism of Esuprone). This enables the enzyme activity to be restored, which contributes to better tolerance of this class of substances. Esuprone thus differs from the known MAO B inhibitors (e.g. tranylcypromine, selegiline), in which enzyme reactivation is not possible (irreversible inhibition).
  • MAO B inhibitors e.g. tranylcypromine, selegiline
  • epilepsy The therapy of the different forms of epilepsy is a problem that has not been solved satisfactorily to date.
  • the antiepileptics available to date in particular temporal rag epilepsy difficult to control.
  • the clinically used anti-epileptics show an abundance of serious side effects, such as sedation, cognitive impairments, the formation of physical drug addiction and liver damage.
  • the invention relates to the use of reversible, selective inhibitors of type A monoamine oxidase for the treatment of epileptic diseases.
  • the invention further relates to the use of reversible, selective inhibitors of type A monoamine oxidase for the production of medicaments for the treatment of epileptic diseases.
  • the above-mentioned Esuprone is particularly suitable as a selective inhibitor.
  • epileptic diseases Generalized or focal cramps as well as temporal lobe epilepsy should be mentioned as epileptic diseases.
  • the inhibitors show a good anticonvulsant effect in a dose which causes MAO inhibition. They are therefore suitable for the treatment of epileptic diseases.
  • the inhibitors can be used both alone and in combination with other known antiepileptics.
  • the dose is usually between 0.3 and 10 mg / kg body weight when administered orally.
  • the substances can be used in the usual galenical forms of application in solid or liquid form, such as tablets, capsules, powders, granules, dragees or solutions. These are manufactured in the usual way.
  • the active ingredients can be mixed with the usual pharmaceutical additives (mainly carriers and diluents) such as talc, gum arabic, sucrose, lactose, corn or corn starch, potato flour, Magnesium stearate, alginates, gum tragacanth, carraghenates, polyvinyl alcohol, polyvinyl pyrrolidones, aqueous or non-aqueous vehicles, wetting agents, dispersants, emulsifiers and / or preservatives can be administered (see H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978 ).
  • the preparations thus obtained normally contain the active ingredient in an amount of 10 to 93 percent by weight.
  • LU 53439 A selective reversible inhibitor of MAO type B, LU 53439, was also examined as a reference substance.
  • LU 53439 inhibits MAO B with an IC 50 of 0.9 nM, MAO A with an IC 50 of approx. 10000 nM. [Drescher et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 347, R135 (1993)].
  • the rat amygdala kindling is currently the most suitable model for complex partial epilepsy in humans. It is based on the progressive development of an epileptic focus through repeated application of small, initially sub-convulsive current impulses in sensitive brain regions (eg amyg- dala) via depth electrodes. In the status of the "fully kindled” (English: fully kindled) animal, the focal epileptic activity then generalizes to other brain areas, and generalized clonic seizures develop [Goddard et al., Exp. Neurol. 25, 295-330 (1969), Löscher et al., Epilepsy Res. 2, 145-181 (1988), Löscher, Curr. Opinion Neurol. Neurosurg. 6, 223-232 (1993)]. In this model, both anti- and proconvulsive substance effects in the focal tissue, as well as in the generalization of convulsive activity in the central nervous system, can be recorded.
  • 500 ⁇ A series (duration 1 s) of monophase rectangular pulses of 1 ms duration, 50 Hz
  • the electroencephalogram ( ⁇ EG) was continuously derived via the depth electrode before and after stimulation. After occurrence of 10 generalized clonic seizures with loss of positioning reflexes [corresponding to stage 5 - focal seizure with secondary generalization - according to Racine, Clin. Neurophysiological 32, 281-294 (1972)], the animals were considered to be "fully chilled”. Childhood was completed by determining the individual electrical spasm threshold 3 times at least 3 days apart.
  • the test of the substance effect consisted of determining the seizure threshold 60, 120 and 240 min after substance application.
  • the control threshold (using the vehicle) was determined 2 or 5 days before each substance test.
  • the individual electrical after-discharge threshold denotes the minimum stimulus amplitude in ⁇ A (further stimulus parameters see above) that was necessary to trigger subsequent discharges of more than 3 s in the amygdala.
  • the animals were stimulated with increasing current strengths at intervals of 1 min (starting 3 steps below the individual stimulus threshold, stimulus increase approx. 20% each).
  • the motor coordination ability on the torsion bar was tested as a parameter for possible side effects (sedation, motor coordination).
  • Esuprone causes a significant increase in spasm threshold as an expression of its anticonvulsant effectiveness. The effect is still detectable 4 hours after application. The effects are statistically significant (one-sided sign test according to Wilcoxon for connected samples). The substance shows no side effects.

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Abstract

The use of reversible, selective inhibitors of monoamine oxidase type A for treating seizure disorders is disclosed.

Description

Verwendung von Hemmstoffen der Monoaminoxidase Typ A zur Behandlung von epileptischen Erkrankungen Use of monoamine oxidase type A inhibitors for the treatment of epileptic diseases
Beschreibungdescription
Die vorliegende Erfindung betrifft die Verwendung von reversiblen, selektiven Hemmstoffen der Monoaminoxidase Typ A zur Behandlung von epileptischen Erkrankungen.The present invention relates to the use of reversible, selective inhibitors of type A monoamine oxidase for the treatment of epileptic diseases.
Ein typisches Beispiel für einen reversiblen, selektiven Hemmstoff der Monoaminoxidase Typ A ist Ξsuprone, der Ethansulfon- säureester des 7 -Hydroxy-3 , 4 -dimethyi -cumarins . Diese Substanz ist als Wirkstoff zur Pharmakotherapie von psychischen Störungen, insbesondere von Depressionen und allergischen Erkrankungen bekannt (EP-OS 111 746, Beispiel 39).A typical example of a reversible, selective inhibitor of type A monoamine oxidase is Ξsuprone, the ethanesulfonic acid ester of 7-hydroxy-3, 4-dimethyl-coumarin. This substance is known as an active ingredient for the pharmacotherapy of mental disorders, in particular depression and allergic diseases (EP-OS 111 746, example 39).
Biochemisch ist Esuprone als ein selektiver und reversibler Hemmstoff der Monoaminoxidase Typ A (MAO A) charakterisiert. Diese Monoaminoxidase ist ein Enzym, das im Organismus von Wirbeltieren für die Inaktivierung von biogenen Aminen wie Noradrenalin, Dop- a in, Serotonin und Phenylethylamin verantwortlich ist. Man unterscheidet zwei Formen des Enzyms nämlich Typ A und Typ 3. Diese unterscheiden sich voneinander durch ihre unterschiedliche Spezi - fität für die genannten biogenen Amine. So wird durch den Typ A überwiegend der Stoffwechsel von Noradrenalin, Dopamin und Serotonin beeinflußt. Esuprone besitzt eine ca. 600fach stärkere Affinität für den Typ A, wie ein Vergleich der ICso-Werte (mittlere Hemmkonzentrationen) für Typ A (IC50 = 8.4 nM) und für Typ B (IC50 = 5000 nM) zeigt [Traut et al . ,Naunyn- Schmiedeberg ' s Arch. Pharmacol. 345, R124 (1992)].Biochemically, Esuprone is characterized as a selective and reversible monoamine oxidase type A (MAO A) inhibitor. This monoamine oxidase is an enzyme that is responsible in the vertebrate organism for the inactivation of biogenic amines such as noradrenaline, dopa- in, serotonin and phenylethylamine. A distinction is made between two forms of the enzyme, namely type A and type 3. These differ from one another by their different specificity for the biogenic amines mentioned. Type A mainly affects the metabolism of noradrenaline, dopamine and serotonin. Esuprone has an affinity for type A that is approx. 600 times stronger, as a comparison of the IC 50 values (mean inhibitory concentrations) for type A (IC 50 = 8.4 nM) and for type B (IC 50 = 5000 nM) shows [Traut et al . , Naunyn-Schmiedeberg's Arch. Pharmacol. 345, R124 (1992)].
Die Hemmung der MAO A durch Esuprone ist reversibel [Traut et al., Naunyn- Schmiedeberg ' s Arch. Pharmacol. 345, R124 (1992)], d.h. die für die Enzymhemmung notwendige Verbindung von Esuprone mit dem E zym ist wieder aufhebbar (beispielsweise durch die Metabolisierung von Esuprone) . Dadurch kann die Enzymaktivität wiederhergestellt werden, was zu einer besseren Verträglichkeit dieser Substanzklasse beiträgt. Esuprone unterscheidet sich damit von den bekannten Hemmstoffen der MAO B (z.B. Tranylcypromin, Selegiline) , bei denen eine Enzymreaktivierung nicht möglich ist (irreversible Hemmung) .The inhibition of MAO A by Esuprone is reversible [Traut et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 345, R124 (1992)], i.e. the connection between Esuprone and the enzyme necessary for enzyme inhibition can be removed (for example by the metabolism of Esuprone). This enables the enzyme activity to be restored, which contributes to better tolerance of this class of substances. Esuprone thus differs from the known MAO B inhibitors (e.g. tranylcypromine, selegiline), in which enzyme reactivation is not possible (irreversible inhibition).
Die Therapie der verschiedenen Epilepsieformen ist ein bisher therapeutisch nicht zufriedenstellend gelöstes Problem. So sind mit den bisher verfügbaren Antiepileptika nicht alle Formen der Epilepsie ausreichend therapierbar, insbesondere sind Temporal- lappenepilepsien schwer zu beherrschen. Weiterhin zeigen die klinisch verwendeten Antiepileptika eine Fülle von gravierenden Nebenwirkungen, wie Sedation, cognitive Beeinträchtigungen, Bildung von physischer Medikamentenabhängigkeit und Leber- Schädigungen.The therapy of the different forms of epilepsy is a problem that has not been solved satisfactorily to date. Thus, not all forms of epilepsy can be adequately treated with the antiepileptics available to date, in particular temporal rag epilepsy difficult to control. Furthermore, the clinically used anti-epileptics show an abundance of serious side effects, such as sedation, cognitive impairments, the formation of physical drug addiction and liver damage.
Es besteht daher das Bedürfnis, Substanzen mit ausreichender Wirkung und geringen Nebenwirkungen zur Behandlung der Epilepsie zur Verfügung zu stellen.There is therefore a need to provide substances with sufficient activity and few side effects for the treatment of epilepsy.
Gegenstand der Erfindung ist die Verwendung von reversiblen, selektiven Hemmstoffen der Monoaminoxidase Typ A, zur Behandlung von epileptischen Erkrankungen.The invention relates to the use of reversible, selective inhibitors of type A monoamine oxidase for the treatment of epileptic diseases.
Gegenstand der Erfindung ist weiter die Verwendung von reversiblen, selektiven Hemmstoffen der Monoaminoxidase Typ A zur Herstellung von Arzneimitteln zur Behandlung von epileptischen Erkrankungen.The invention further relates to the use of reversible, selective inhibitors of type A monoamine oxidase for the production of medicaments for the treatment of epileptic diseases.
Als reversible, selektive Hemmstoffe der Monoaminoxidase Typ A eignen sich beispielsweise Moclobemide (Merck-Index, 12. Auflage 1996, Nr. 6309) und Brofaromine [= CGP 11 305A, Eur.J. Pharmacol. 94, 73 + 101(1983)]. Insbesondere eignet sich das oben genannte Esuprone als selektiver Hemmstoff.Suitable reversible, selective inhibitors of type A monoamine oxidase are, for example, moclobemides (Merck Index, 12th edition 1996, No. 6309) and brofaromines [= CGP 11 305A, Eur.J. Pharmacol. 94, 73 + 101 (1983)]. The above-mentioned Esuprone is particularly suitable as a selective inhibitor.
Als epileptische Erkrankungen sind insbesondere generalisierte oder fokale Krämpfe sowie Temporallappenepilepsien zu nennen.Generalized or focal cramps as well as temporal lobe epilepsy should be mentioned as epileptic diseases.
Die Hemmstoffe zeigen im Tierexperiment in einer Dosis, die eine MAO Hemmung bewirkt, eine gute antikonvulsive Wirkung. Sie eignen sich daher zur Behandlung von epileptischen Erkrankungen. Die Hemmstoffe können sowohl allein, als auch in Kombination mit anderen, bekannten Antiepileptika angewendet werden.In animal experiments, the inhibitors show a good anticonvulsant effect in a dose which causes MAO inhibition. They are therefore suitable for the treatment of epileptic diseases. The inhibitors can be used both alone and in combination with other known antiepileptics.
Sie können in üblicher Weise, z.B. oral oder intravenös verabreicht werden. Die orale Gabe ist bevorzugt.You can in the usual way, e.g. administered orally or intravenously. Oral administration is preferred.
Die Dosis beträgt in der Regel zwischen 0,3 und 10 mg/kg Körpergewicht bei oraler Gabe.The dose is usually between 0.3 and 10 mg / kg body weight when administered orally.
Die Substanzen können in den üblichen galenischen Applikations- formen fest oder flüssig angewendet werden, wie Tabletten, Kapseln, Pulver, Granulate, Dragees oder Lösungen. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den gebräuchlichen galenischen Hilfsmitteln (hauptsächlich Träger- und Verdünnungsmitteln) wie Talkum, Gummi arabikum, Saccharose, Lactose, Getreide- oder Maisstärke, Kartoffelmehl, Magnesiumstearat, Alginaten, Gummi-Tragacanth, Carraghenaten, Polyvinylalkohol, Polyvinylpyrrolidonen, wäßrigen oder nicht wäßrigen Trägern, Netzmitteln, Dispergiermitteln, Emulgatoren und/oder Konservierungsmitteln verabreicht werden (vgl. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978) . Die so erhaltenen Präparate enthalten den Wirkstoff normalerweise in einer Menge von 10 bis 93 Gewichtsprozent.The substances can be used in the usual galenical forms of application in solid or liquid form, such as tablets, capsules, powders, granules, dragees or solutions. These are manufactured in the usual way. The active ingredients can be mixed with the usual pharmaceutical additives (mainly carriers and diluents) such as talc, gum arabic, sucrose, lactose, corn or corn starch, potato flour, Magnesium stearate, alginates, gum tragacanth, carraghenates, polyvinyl alcohol, polyvinyl pyrrolidones, aqueous or non-aqueous vehicles, wetting agents, dispersants, emulsifiers and / or preservatives can be administered (see H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978 ). The preparations thus obtained normally contain the active ingredient in an amount of 10 to 93 percent by weight.
Die therapeutische Wirkung der reversiblen, selektiven Hemmstoffe der Monoaminoxidase Typ A bei epileptischen Erkrankungen wird durch die nachfolgenden Versuche belegt, in denen Esuprone verwendet wurde.The therapeutic effect of the reversible, selective inhibitors of monoamine oxidase type A in epileptic diseases is demonstrated by the subsequent experiments in which Esuprone was used.
Als Vergleichssubstanz wurde eine selektiver reversibler Hemm- stoff der MAO Typ B, LU 53439, mituntersucht. LU 53439 hemmt die MAO B mit einer IC50 von 0.9 nM, die MAO A mit einer IC50 von ca. 10000 nM. [Drescher et al., Naunyn-Schmiedeberg' s Arch. Pharmacol. 347, R135 (1993)].A selective reversible inhibitor of MAO type B, LU 53439, was also examined as a reference substance. LU 53439 inhibits MAO B with an IC 50 of 0.9 nM, MAO A with an IC 50 of approx. 10000 nM. [Drescher et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 347, R135 (1993)].
Amygdala-Kindling-ModellAmygdala-Kindling model
Das Amygdala-Kindling der Ratte stellt zur Zeit das am besten geeignete Modell für komplex-partielle Epilepsien des Menschen dar. Es basiert auf der progressiven Entwicklung eines epileptischen Focus durch wiederholte Applikation von geringen, zunächst sub- convulsiven Stromimpulsen in sensible Gehirnregionen (z.B. Amyg- dala) über Tiefenelektroden. Im Status des "vollgekindelten" (englisch: fully kindled) Tieres generalisiert die fokale epileptische Aktivität dann auch in andere Hirnbereiche, und es kommt zur Ausbildung generalisierter klonischer Anfälle [Goddard et al., Exp. Neurol. 25, 295-330 (1969), Löscher et al.,Epilepsy Res. 2, 145-181 (1988), Löscher, Curr. Opinion Neurol . Neurosurg. 6, 223-232 (1993)]. In diesem Modell können sowohl anti- als auch prokonvulsive Substanzwirkungen im fokalen Gewebe, wie auch bei der Generalisation der Krampfaktivität im zentralen Nervensystem erfaßt werden.The rat amygdala kindling is currently the most suitable model for complex partial epilepsy in humans. It is based on the progressive development of an epileptic focus through repeated application of small, initially sub-convulsive current impulses in sensitive brain regions (eg amyg- dala) via depth electrodes. In the status of the "fully kindled" (English: fully kindled) animal, the focal epileptic activity then generalizes to other brain areas, and generalized clonic seizures develop [Goddard et al., Exp. Neurol. 25, 295-330 (1969), Löscher et al., Epilepsy Res. 2, 145-181 (1988), Löscher, Curr. Opinion Neurol. Neurosurg. 6, 223-232 (1993)]. In this model, both anti- and proconvulsive substance effects in the focal tissue, as well as in the generalization of convulsive activity in the central nervous system, can be recorded.
Die Versuche wurden an weiblichen Wistar-Ratten durchgeführt. Den Tieren wurde in Chloralhydrat-Narkose eine bipolare Tiefenelek- trode aus Edelstahl in die rechte basolaterale Amygdala implantiert [2.2 mm caudal, 4.8 mm lateral und 8.5 mm ventral vom Bregma, Koordinaten nach Paxinos und Watson: The rat brain in stereotaxic coordinates, Academic Press, New York (1986)]. Nach einer 2-wöchigen postoperativen Erholung wurde mit der täglichen Stimulation der Tiere begonnen, wobei ein konstanter supramaximaler Reiz von 500 μA (Serie (Dauer 1 s) von monophasisehen Rechteckimpulsen von 1 ms Dauer, 50 Hz) über die Tiefenelektrode ver- abreicht wurde. Über die Tiefenelektrode wurde vor und nach Stimulation kontinuierlich das Elektroencephalogramm (ΞEG) abgeleitet. Nach Auftreten vom 10 generalisierten klonischen Anfällen mit Verlust der Stellreflexe [entsprechend Stadium 5 - fokaler Anfall mit sekundärer Generalisation- nach Racine, Clin. Neuro- physiol. 32, 281-294 (1972)] wurden die Tiere als "vollgekindelt" betrachtet. Das Aufkindein wurde mit der 3-maligen Bestimmung der individuellen elektrischen Krampfschwelle im Abstand von mindestens 3 Tagen abgeschlossen.The experiments were carried out on female Wistar rats. In chloral hydrate anesthesia, the animals were implanted with a deep bipolar stainless steel electrode in the right basolateral amygdala [2.2 mm caudal, 4.8 mm lateral and 8.5 mm ventral from the bregma, coordinates according to Paxinos and Watson: The rat brain in stereotaxic coordinates, Academic Press , New York (1986)]. After a 2-week postoperative recovery, daily stimulation of the animals was started, with a constant supramaximal stimulus of 500 μA (series (duration 1 s) of monophase rectangular pulses of 1 ms duration, 50 Hz) via the depth electrode. was handed over. The electroencephalogram (ΞEG) was continuously derived via the depth electrode before and after stimulation. After occurrence of 10 generalized clonic seizures with loss of positioning reflexes [corresponding to stage 5 - focal seizure with secondary generalization - according to Racine, Clin. Neurophysiological 32, 281-294 (1972)], the animals were considered to be "fully chilled". Childhood was completed by determining the individual electrical spasm threshold 3 times at least 3 days apart.
Die Prüfung der Substanzwirkung bestand in der Krampfschwellen- bestimmung 60, 120 und 240 min nach Substanzapplikation. 2 bzw. 5 Tage vor jedem Substanzversuch wurde die Kontrollschwelle (unter Applikation des Vehikels) bestimmt.The test of the substance effect consisted of determining the seizure threshold 60, 120 and 240 min after substance application. The control threshold (using the vehicle) was determined 2 or 5 days before each substance test.
Während der Versuche wurden folgende Parameter bestimmt:The following parameters were determined during the tests:
Die individuelle elektrische Nachentladungsschwelle (after- discharge threshold, ADT) bezeichnet die minimale Reiz- amplitude in μA (weitere Reizparameter s.o.), die nötig war, um Nachentladungen von mehr als 3 s Dauer in der Amygdala auszulösen. Hierbei wurden die Tiere im Abstand von 1 min mit aufsteigenden Stromstärken (beginnend 3 Stufen unter der individuellen Reizschwelle, Reizzunahme jeweils ca. 20%) gereizt.The individual electrical after-discharge threshold (ADT) denotes the minimum stimulus amplitude in μA (further stimulus parameters see above) that was necessary to trigger subsequent discharges of more than 3 s in the amygdala. The animals were stimulated with increasing current strengths at intervals of 1 min (starting 3 steps below the individual stimulus threshold, stimulus increase approx. 20% each).
Als ein Parameter für möglicherweise auftretende Nebenwirkungen (Sedation, motorische Koordination) wurde die motorische Koordinationsfähigkeit am Drehstab (rotierender Stab mit 8 Umdrehungen/min; Kontrolltiere können sich mindestens 1 min auf dem Stab halten) geprüft.The motor coordination ability on the torsion bar (rotating bar at 8 revolutions / min; control animals can stay on the bar for at least 1 min) was tested as a parameter for possible side effects (sedation, motor coordination).
ie Ergebnisse sind in Tabelle 1 zusammengefaßt. The results are summarized in Table 1.
Tabelle 1Table 1
Wirkung von Esuprone auf die Nachentladungsschwelle von gekindel- ten RattenEffect of Esuprone on the post-discharge threshold of clipped rats
Figure imgf000007_0001
Figure imgf000007_0001
* statistisch signifikant p< 0.05* statistically significant p <0.05
Esuprone bewirkt eine deutliche KrampfSchwellenerhöhung als Ausdruck seiner antikonvulsiven Wirksamkeit. Der Effekt ist auch noch 4 Stunden nach Applikation nachweisbar. Die Wirkungen sind statistisch signifikant (einseitiger Vorzeichentest nach Wilcoxon für verbundene Stichproben) . Die Substanz zeigt keinerlei Nebenwirkung.Esuprone causes a significant increase in spasm threshold as an expression of its anticonvulsant effectiveness. The effect is still detectable 4 hours after application. The effects are statistically significant (one-sided sign test according to Wilcoxon for connected samples). The substance shows no side effects.
Weiterhin wurde gefunden, daß bei Stimulation der Tiere mit einer Stromstärke, die 20% über der individuellen Kontrollkrampf - schwelle liegt, 70-80% der Tiere 1-2 Stunden nach Applikation von 20 mg/kg Esuprone vollständig vor fokalen und generalisierten Anfällen geschützt waren.Furthermore, it was found that when the animals were stimulated with a current strength that is 20% above the individual control spasm threshold, 70-80% of the animals were completely protected against focal and generalized attacks 1-2 hours after application of 20 mg / kg Esuprone .
Für eine Dosis von 10 mg/kg p.o. konnte im Rattenhirn eine 85 %ige Hemmung der Monoaminoxidase Typ A gefunden werden [Traut et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 345, R124 (1992)]. Für die geprüfte Dosis von 20 mg/kg p.o. kann also eine maximale Hemmung der MAO A angenommen werden.For a dose of 10 mg / kg p.o. an 85% inhibition of monoamine oxidase type A was found in the rat brain [Traut et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 345, R124 (1992)]. For the tested dose of 20 mg / kg p.o. a maximum inhibition of MAO A can be assumed.
Der vergleichend geprüfte selektive Hemmer der MAO B, Lü 53439, zeigt keinerlei antikonvulsive Wirkung, was die Spezifität der MAO A-Hemmung für die antikonvulsive Wirksamkeit beweist. The comparative tested selective inhibitor of MAO B, Lü 53439, shows no anticonvulsive effect, which proves the specificity of MAO A inhibition for the anticonvulsive activity.

Claims

Patentansprüche claims
1. Verwendung von reversiblen, selektiven Hemmstoffen der Mono- aminoxidase Typ A zur Behandlung von epileptischen Erkrankungen.1. Use of reversible, selective inhibitors of monoamine oxidase type A for the treatment of epileptic diseases.
2. Verwendung gemäß Anspruch 1, dadurch gekennzeichnet daß man als reversiblen, selektiven Hemmstoff der Monoaminoxidase Typ A Esuprone verwendet.2. Use according to claim 1, characterized in that Esuprone is used as the reversible, selective inhibitor of type A monoamine oxidase.
3. Verwendung von reversiblen, selektiven Hemmstoffen der Monoaminoxidase Typ A zur Herstellung von Arzneimitteln zur Behandlung von epileptischen Erkrankungen.3. Use of reversible, selective inhibitors of type A monoamine oxidase for the production of medicaments for the treatment of epileptic diseases.
Verwendung von Esuprone zur Herstellung eines Arzneimittels zur Behandlung von epileptischen Erkrankungen. Use of Esuprone in the manufacture of a medicament for the treatment of epileptic diseases.
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