NMDA antagonist comprising xenon

Details NMDA antagonist comprising xenon NMDA antagonist comprising xenon

2001-06-14

2003-11-25

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated inorganic nonactive ingredient or elemental...

C424S600000, C514S220000, C514S731000, C514S759000, C514S812000, C514S816000, C514S959000

Reexamination Certificate

active

06653354

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not Applicable
BACKGROUND OF THE INVENTION
The present invention relates to the use of xenon as a neuroprotectant and/or in the inhibition of synaptic plasticity, and/or for relieving neuropathic pain. In particular, the invention relates to the use of xenon as an NMDA antagonist, and its use in the treatment of conditions associated with NMDA receptor activity.
The NMDA (N-methyl-D-aspartate) receptor is a major subclass of glutamate receptor and glutamate is believed to be the most important excitatory neurotransmitter in the mammalian central nervous system. Importantly, activation of the NMDA receptor has been shown to be the central event which leads to excitotoxicity and neuronal death in many disease states, as well as a result of hypoxia and ischaemia following head trauma, stroke and following cardiac arrest.
It is known in the art that the NMDA receptor plays a major role in the synaptic plasticity which underlies many higher cognitive functions, such as memory and learning, as well as in certain nociceptive pathways and in the perception of pain (Collingridge et al, The NMDA Receptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain which underlies consciousness itself.
NMDA receptor antagonists are therapeutically valuable for a number of reasons, such as the following three specific reasons. Firstly, NMDA receptor antagonists confer profound analgesia, a highly desirable component of general anaesthesia and sedation. Secondly, NMDA receptor antagonists are neuroprotective under many clinically relevant circumstances (including ischemia, brain trauma, neuropathic pain states, and certain types of convulsions). Thirdly, NMDA receptor antagonists confer a valuable degree of amnesia.
However, it is clear from the prior art that there are a number of drawbacks associated with current NMDA receptor antagonists. These include the production of involuntary movements, stimulation of the sympathetic nervous system, induction of neurotoxicity at high doses (which is pertinent since NMDA receptor antagonists have low potencies as general anaesthetics), depression of the myocardium, and proconvulsions in some epileptogenic paradigms e.g., “kindling” (Wlaz P et al, Eur. J. Neurosci. 1994; 6:1710-1719). In particular, there have been considerable difficulties in developing new NMDA receptor antagonists that are able to cross the blood-brain barrier. This factor has also limited the therapeutic applications of many known NMDA antagonists.
The present invention thus seeks to provide an improved NMDA receptor antagonist for general pharmaceutical use which can readily diffuse across the blood brain barrier.
BRIEF SUMMARY OF THE INVENTION
In a broad aspect, the present invention relates to the use of xenon as a neuroprotectant and/or as an inhibitor of synaptic plasticity. In a preferred aspect, the xenon acts as an NMDA receptor antagonist.
A second aspect of the present invention relates to a method of treatment comprising modulating the activity of an NMDA receptor in a mammal, the method comprising modulating the activity of the NMDA receptor by administering to the mammal a therapeutically effective amount of xenon.
In a preferred aspect of the invention, the xenon is administered in combination with a pharmaceutically acceptable carrier, diluent or excipient.
Preferably, the method of treatment may be used to treat a mammal suffering from a condition associated with NMDA receptor activity. In a more preferred aspect, the mammal is treated for a condition that is associated with NMDA receptor activation.
Even more preferably, the present invention relates to a method of treatment wherein the xenon reduces the level of activation of the NMDA receptor.
Another embodiment of the invention relates to a process for the preparation of a pharmaceutical composition suitable for modulating the activity of an NMDA receptor, which process comprises adding an NMDA antagonist to a pharmaceutically acceptable carrier, excipient or diluent, wherein the improvement comprises using xenon as the NMDA antagonist.
A further embodiment of the present invention provides a pharmaceutical composition for modulating NMDA activity which comprises an NMDA antagonist and a pharmaceutically acceptable carrier, excipient or diluent, wherein the improvement comprises using xenon as the NMDA antagonist.
Yet another embodiment of the invention relates to the use of xenon in the preparation of a pharmaceutical for use in modulating the activity of an NMDA receptor in a mammal.
In a preferred aspect, the xenon in the pharmaceutical is used in combination with a pharmaceutically acceptable carrier, diluent or excipient.
Preferably, the pharmaceutical is for use in treating a condition associated with NMDA receptor activity. In a more preferred aspect, the pharmaceutical is for use in treating a condition associated with NMDA receptor activation. Even more preferably, the pharmaceutical is for use in reducing the level of activation of the NMDA receptor.
The present invention also provides a pharmaceutical composition suitable for providing neuroprotection, inhibiting synaptic plasticity or relieving neuropathic pain, said composition comprising xenon and a GABAergic agent admixed with a pharmaceutically acceptable carrier, excipient or diluent.
In a preferred embodiment of the invention, said GABAergic agent is a sedative or an anaesthetic.
In a particularly preferred embodiment of the invention, said GABAergic agent is selected from the group consisting of a benzodiazepine, propofol, isoflurane, and mixtures thereof.
The present invention further relates to a process for the preparation of a pharmaceutical composition suitable for providing neuroprotection, inhibiting synaptic plasticity or relieving neuropathic pain, which process comprises adding xenon and a GABAergic agent to a pharmaceutically acceptable carrier, excipient or diluent.
Another aspect of the invention relates to the use of xenon as a neuroprotectant, for inhibiting synaptic plasticity, or for relieving neuropathic pain.
In a preferred embodiment of this aspect of the invention, the xenon is an NMDA antagonist.
In an even more preferred embodiment, the xenon is used in combination with a GABAergic agent.
In one particularly preferred embodiment, the GABAergic agent is selected from the group consisting of a benzodiazepine, propofol, isoflurane, and mixtures thereof.
Another aspect of the invention relates to a method for modulating the activity of an NMDA receptor in a mammal comprising administering to the mammal xenon in amounts effective to modulate the activity of said receptor.
Preferably, the xenon is administered in combination with a pharmaceutically acceptable carrier, diluent or excipient.
Even more preferably, the xenon is administered in combination with a GABAergic agent.
In a particularly preferred embodiment of the invention, the GABAergic agent is selected from the group consisting of a benzodiazepine, propofol, isoflurane, and mixtures thereof.
In one preferred embodiment, the mammal is treated for a condition associated with NMDA receptor activity.
In another preferred embodiment, the mammal is treated for a condition associated with NMDA receptor activation.
In a particularly preferred embodiment, the xenon reduces the level of activation of the NMDA receptor.
Yet another aspect of the invention provides a pharmaceutical composition suitable for providing neuroprotection, inhibiting synaptic plasticity or relieving neuropathic pain, said composition comprising xenon and a GABAergic agent admixed with a pharmaceutically acceptable carrier, excipient or diluent, wherein said xenon and said GABAergic agent are present in an amount sufficient to provide neuroprotection, inhibit synaptic plasticity or relieve neuropathic pain.
A further aspect of the invention relates to a method for modulating the activity of an NMDA receptor in a mammal comprising administering to the mam

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