U.S. patent application number 10/342968 was filed with the patent office on 2003-09-25 for use of xenon for treating neurointoxications.
This patent application is currently assigned to AGA AB. Invention is credited to Kox, Wolfgang J., Petzelt, Christian.
Application Number | 20030180375 10/342968 |
Document ID | / |
Family ID | 7900688 |
Filed Date | 2003-09-25 |
United States Patent
Application |
20030180375 |
Kind Code |
A1 |
Petzelt, Christian ; et
al. |
September 25, 2003 |
Use of xenon for treating neurointoxications
Abstract
Methods for treating mammals for neurointoxication are provided
comprising treating the mammal with a xenon-containing gas. Methods
of providing neuroprotection in mammals are also disclosed
comprising administering therapeutically effective amounts of
xenon, preferably in combination with pharmaceutically acceptable
carriers, diluents or excipients.
Inventors: |
Petzelt, Christian; (Berlin,
DE) ; Kox, Wolfgang J.; (Berlin, DE) |
Correspondence
Address: |
LERNER, DAVID, LITTENBERG,
KRUMHOLZ & MENTLIK
600 SOUTH AVENUE WEST
WESTFIELD
NJ
07090
US
|
Assignee: |
AGA AB
Lidingo
SE
|
Family ID: |
7900688 |
Appl. No.: |
10/342968 |
Filed: |
January 15, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10342968 |
Jan 15, 2003 |
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09936319 |
Dec 19, 2001 |
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6559190 |
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09936319 |
Dec 19, 2001 |
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PCT/EP00/02025 |
Mar 8, 2000 |
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Current U.S.
Class: |
424/600 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 9/00 20180101; A61P 27/16 20180101; A61P 25/16 20180101; A61P
15/00 20180101; A61P 25/18 20180101; A61P 25/06 20180101; A61P
25/30 20180101; A61P 17/02 20180101; A61P 43/00 20180101; A61P
25/00 20180101; A61K 33/00 20130101 |
Class at
Publication: |
424/600 |
International
Class: |
A61K 033/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 11, 1999 |
DE |
199 10 986.9 |
Claims
1. A treatment method comprising using xenon as a
neuroprotectant.
2. A method of providing neuroprotection in a mammal, said method
comprising administering to said mammal a therapeutically effective
amount of xenon.
3. The method of claim 2 including administering said xenon in
combination with a compound selected from the group consisting of
pharmaceutically acceptable carriers, diluents and excipients.
4. The method of claim 2 comprising treating said mammal for a
condition associated with NMDA receptor activity.
5. The method of claim 2 comprising treating said mammal for a
condition associated with NMDA receptor activation.
6. The method of claim 2 wherein said xenon reduces the level of
activation of the NMDA receptor.
7. A process for the preparation of a pharmaceutical composition
suitable for neuroprotection, said process comprising adding xenon
to a component selected from the group consisting of
pharmaceutically acceptable carriers, excipients and diluents, and
using said xenon as a neuroprotectant.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of U.S. patent application Ser. No.
09/936,319, filed on Dec. 19, 2001.
FIELD OF THE INVENTION
[0002] The present invention relates to the use of xenon for
treating neurointoxications. More particularly, the present
invention relates to a use of xenon in which the neurointoxication
is caused by a neurotransmitter excess.
BACKGROUND OF THE INVENTION
[0003] The uncontrolled release of neurotransmitters, particularly
glutamate, noradrenalin and dopamine, is responsible for many acute
and chronic intoxications of the brain. These are called
neurointoxications or neuropoisonings. These neurotransmitters kill
the affected neurons either by induction of apoptosis (controlled
cell death) and/or secondarily by their metabolites, by forming
oxygen radicals which in turn have toxic effects. An uncontrolled
release of neurotransmitters which result in a strongly increased
concentration of the neurotoxins in the affected tissue, can be due
to various endogenous or exogenous causes. For example, an
increased release of glutamate or dopamine may result in an acute
craniocerebral trauma. An increase in the neurotransmitter release
has also been observed as a response to oxygen deficiency in the
brain, e.g. in the case of apoplexy (ischemia) or in the case of
other hypoxias, particularly during childbirth. Drug abuse
represents another cause of impaired neurotransmitter release. In
certain forms of schizophrenia, stress-induced relapses back into
schizophrenia (acute episodes) are also accompanied by increased
neurotransmitter release. Finally, a chronic shift of
neurotransmitter balance, particularly of dopamine balance, has
also been observed in various regions of the brain in the case of
Parkinson's disease. Increased dopamine release and subsequent
formation of free radicals occur in that case as well. Various
investigations made with cell cultures and experimental animals
have proven the release of neurotransmitters, particularly as a
result of oxygen deficiency.
[0004] For example, it can be shown that in rats into which the
dopamine neurotoxin 6-hydroxy-dopamine was infused unilaterally
into the substantia nigra, which resulted in a unilateral depletion
of dopamine in the ipsilateral striatum, an experimentally induced
ischemia in the regions of dopamine depletion led to damage which
was less than that in other regions of the brain. These results
suggest that dopamine plays a part in ischemia-induced striatal
cell death (Clemens and Phebus, Life Science, Vol. 42, p. 707 et
seq., 1988).
[0005] It can also be shown that dopamine is released in great
amounts from the striatum during cerebral ischemia (Kahn et al.,
Anest.-Analg., Vol. 80, p. 1116 et seq., 1995).
[0006] The release of neurotransmitters during cerebral ischemia
was investigated in detail and seems to play a key role for
excitotoxic neural death. For example, Kondoh et al., Neurosurgery,
Vol. 35, p. 278 et seq., 1994, showed that changes in the
neurotransmitter release and metabolization can reflect changes in
the cellular metabolism during ischemia. The increase in the
extracellular dopamine concentration in the striatum of
experimental animals in which experimental apoplexies were induced,
is well documented.
[0007] The contribution of excess dopamine to neuronal damage can
be derived from the ability of dopamine antagonists to obtain
protection of the neurons in ischemia models (Werling et al., Brain
Research, Vol. 606, p. 99 et seq., 1993). In a cell culture,
dopamine primarily causes apoptosis of striatal neurons, without
damaging the cells by a negative effect on the oxidative
phosphorylation the (ATP/ADP ratio remains unchanged). However, if
its effect is combined with a minimum inhibition of mitochondrial
functions, the neurotoxic effect of dopamine will be increased
significantly (McLaughlin et al., Journal of Neurochemistry, Vol.
70, p. 2406 et seq., 1998).
[0008] In addition to the direct hypoxic toxicity on neurons, the
stress induced by oxygen deficiency, particularly during a birth,
effects an increased dopamine release, which results in a negative
conditioning of the brain for dopaminergic regulations. This means
that even children who seem to survive a hypoxic birth phase
uninjured, have a tendency towards convulsions and epileptic
conditions when they are older.
[0009] Another cause of a disturbed neurotransmitter release is
represented by drug abuse. In particular, if drugs such as designer
drugs (e.g. ecstasy, etc.) or heroin are consumed, and amphetamines
are overdosed, the persons will show signs of intoxication and
often spasmophilia, which is based on an increased neurotransmitter
release.
[0010] The causes of schizophrenia are also due to a complex
impairment of the neurotransmitter regulation. Schizophrenia
patients are often asymptomatic over a prolonged period of time,
but they have a tendency towards spontaneous schizophrenia attacks
which are obviously triggered by a stress-induced dopamine release,
even in minor stress situations. Here, one speaks of catatonic
schizophrenia. Further neuropsychiatric diseases which are based on
an increased neurotransmitter release are depressions and Gilles de
la Tourette syndrome ("maladie de tics", "Tics impulsif").
[0011] Finally, one cause of Parkinson's disease is presently
believed to be in dopamine modulation and in dopamine metabolism.
In Parkinson's disease, dopaminergic neurons in the striatum are
especially damaged. References exist to the effect that Parkinson's
disease is caused by a dopamine excess in the affected region of
the posterolateral hypothalamus and the substantia nigra. Many
neurons which have lost their functionality but not their vitality
are found in this region. These neurons, referred to as "orphan
neurons," continuously release neurotransmitter amounts having
pathologic effects.
[0012] With the exception of Parkinson's disease, where dopa
precursors are used as preparations, basically of schizophrenia, no
therapeutic approaches presently exist which focus on a reduction
of the dopamine concentration in the environment of endangered
cells.
[0013] Therefore, there is a demand for a preparation which reduces
or prevents the damaging effects of uncontrolled neurotransmitter
release, e.g. of dopamine, glutamate or noradrenalin, from neurons.
It is therefore an object of the present invention to provide such
a preparation which can be of use in the above-mentioned, as well
as in other fields of application.
SUMMARY OF THE INVENTION
[0014] In accordance with the present invention, these and other
objects have now been realized by the discovery of a method for
treating a mammal for neurointoxication comprising treating the
mammal with a xenon-containing gas. Preferably, the
xenon-containing gas comprises a mixture of gases.
[0015] In accordance with one embodiment of the method of the
present invention, the neurointoxication is caused by an excess of
neurotransmitter in the mammal.
[0016] In accordance with another embodiment of the method of the
present invention, treating of the mammal with the xenon-containing
gas comprises reducing the release of neurotransmitters in the
mammal. Preferably, the neurotransmitters are dopamine, glutamate
and/or noradrenalin.
[0017] In accordance with another embodiment of the method of the
present invention, the neurointoxication is caused by apoplexy. In
other embodiments, the neurointoxication is caused by drug abuse,
oxygen deficiency during birth, a craniocerebral trauma, loss of
hearing, or migraine.
[0018] In accordance with another embodiment of the method of the
present invention, the neurointoxication is correlated with a
condition such as Parkinson's disease, schizophrenia, or Gilles de
la Tourette syndrome.
[0019] In accordance with another embodiment of the method of the
present invention, the treating of the mammal with the
xenon-containing gas comprises using a cardio-pulmonary bypass
machine.
[0020] In accordance with another embodiment of the method of the
present invention, the xenon-containing gas comprises an
administered preparation containing from 5 to 90% by volume of the
xenon.
[0021] In accordance with another embodiment of the method of the
present invention, the xenon-containing gas comprises an
administered preparation containing from 5 to 30% by volume of the
xenon.
[0022] In accordance with another embodiment of the method of the
present invention, the xenon-containing gas comprises an
administered preparation containing a gas such as oxygen, nitrogen
or air. Preferably, the xenon-containing gas comprises oxygen, and
the ratio of the xenon to the oxygen is from about 80 to 20% by
volume.
[0023] In accordance with another aspect of the present invention,
a treatment method has been discovered comprising using xenon as a
neuroprotectant.
[0024] In accordance with yet another aspect of the present
invention, a method of providing neuroprotection in a mammal has
been discovered, the method comprising administering to the mammal
a therapeutically effective amount of xenon. Preferably, the method
includes administering the xenon in combination with a compound
such as a pharmaceutically acceptable carrier, diluent and/or
excipient.
[0025] In accordance with another embodiment of this method of the
present invention, the method includes treating the mammal for a
condition associated with NMDA receptor activity.
[0026] In accordance with another embodiment of this method of the
present invention, the method includes treating the mammal for a
condition associated with NMDA receptor activation.
[0027] In accordance with another embodiment of this method of the
present invention, the xenon reduces the level of activation of the
NMDA receptor.
[0028] In accordance with yet another aspect of the present
invention, a process has been provided for the preparation of a
pharmaceutical composition suitable for neuroprotection, the
process comprising adding xenon to a component such as a
pharmaceutically acceptable carrier, excipient and/or diluent, and
using the xenon as a neuroprotectant.
[0029] In accordance with the present invention, it has been found
that the noble gas xenon surprisingly now reversibly suppresses the
release of neurotransmitters, particularly dopamine and glutamate.
This unexpected discovery has thus created the possibility of
producing preparations for treating cell damage and diseases,
respectively, which are caused by an increased neurotransmitter
release, and particularly dopamine release or glutamate
release.
[0030] Correspondingly, the present invention generally relates to
the use of xenon for treating neurointoxications, and on the
production of a preparation containing xenon for treating
neurointoxications, respectively. The present invention also
relates to the preparations per se and to a method of producing
same. Such neurointoxications particularly concern an excess of
neurotransmitter. The present invention is particularly based on
the insight that xenon reduces the release of dopamine and/or
glutamate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] The present invention may be more fully appreciated with
reference to the following detailed description, which, in turn,
refers to the Figures wherein:
[0032] FIG. 1A is a graphical representation of the release of
dopamine under various hypoxic situations;
[0033] FIG. 1B is a graphical representation of relative dopamine
concentration as a result of various hypoxic situations; and
[0034] FIG. 2 is a graphical representation showing release of
dopamine in various stress situations.
DETAILED DESCRIPTION
[0035] According to the present invention neurointoxications are
understood to mean acute or chronic "states of poisoning" of the
central nervous system (CNS), and particularly of the brain, which
in most cases result in severe deficiency symptoms of the affected
areas. These states of poisoning result from an excess of
neurotransmitter, particularly of glutamate, noradrenalin and/or
dopamine, which can be due to a variety of causes. The
above-mentioned diseases, such as apoplexy, hypoxias, oxygen
deficiency during a birth, Parkinson's disease, craniocerebral
trauma, drug abuse, schizophrenia, depressions and Gilles de la
Tourette syndrome are among those that can be mentioned here. The
inventors have also found that patients who must be connected to a
cardio-pulmonary bypass machine often suffer from cerebral
deficiency symptoms which are due to an excess of neurotransmitter
caused by hypoxia. For example, the use of a cardio-pulmonary
bypass machine can cause an often unidentified neurointoxication,
which delays the patient's reconvalecence to a considerable extent.
It has also been found that any prolonged artificial respiration
can result in undesired neurointoxication as a side-effect. In
recent investigations conducted by the inventors, the surprising
insight has been gained that the hearing loss (e.g. due to noise,
presbycusis, tinnitus, or sudden deafness) can also be caused by
neurointoxication. The excess neurotransmitter release,
particularly excessive glutamate and dopamine release, which can
have been caused e.g. by an impairment in the body, an acoustic
trauma, or an ischemia, results in an acute destruction of the
nerve endings and subsequently death of the corresponding nerves in
the hearing organs. Migraine has to be considered another disease
which is most likely due to an impaired dopamine balance, and thus
to neurointoxication.
[0036] The discovery that the neurotransmitter release can be
influenced by xenon enables an entirely new field of application
for this noble gas, which has up to now been used increasingly as
an inhalation anesthetic agent in the field of anesthetics. The
treatment of the differing neurotransmitter excess diseases of the
brain, such as those discussed above, can be carried out on the
basis of the present invention by a simple inhalation therapy. The
uptake of xenon by means of the respiratory system, and transport
into the brain, are already proved by its use as anesthetic agent.
It can also be assumed that the use of xenon has no damaging effect
on the human organism, since many corresponding experiences can be
realized by its use as an anesthetic agent. Xenon can be applied by
various techniques, which can be chosen as a function of the
location of use. For example, inhaling apparatus can be used in the
clinics, which are also used for anesthesia by inhalation. If a
cardio-pulmonary bypass machine or other artificial breathing
apparatus is used, xenon can be added directly in the machine, and
thus requires no further apparatus. In this case, standard xenon
addition can prevent the formation of neurointoxications in the
model case (prophylaxis) or at least reduce the deficiency
symptoms. On an ambulant basis, e.g. in the primary treatment of
victims of an accident, it is possible to use simpler inhalators
which mix the xenon with the ambient air during the process of
inhalation. In this connection, it is also possible to adapt the
xenon concentration and the timing of xenon use, a in simple
manner, to the therapeutic requirements. For example, it is
advantageous to use mixtures of xenon with other gases, it being
possible to mix the xenon with oxygen, nitrogen, air or other gases
which are harmless for humans.
[0037] In patients suffering from a severe craniocerebral trauma,
respiration with a xenon-oxygen mixture, as also used in
anesthesia, can prevent, or at least reduce, the release of
dopamine and thus the secondary neurotoxic effects accompanying
this trauma. In such accidents, the additional anesthetic
side-effect is desired, since the patient can be freed from pain
thereby.
[0038] An essential feature of acute ischemia in the brain is
represented by the secondary neurotoxic effects which form by an
increase in the neurotransmitter release, and are responsible for
the death of the neurons in the ischemic marginal region. Although
an immediate xenon treatment, e.g. by the emergency physician who
carries out the initial treatment in the case of an apoplexy
patient, cannot prevent ischemia per se, but it can at least
reduce, or even prevent, the neurotoxicity by the secondarily
released neurotransmitters. Thus, the permanent damage frequently
occurring in the case of apoplexy can be reduced. The same applies
analogously to measures which will have to be taken if disease
symptoms occur after drug abuse and loss of hearing, or a migraine
attack.
[0039] In the case of oxygen deficiency during a birth, e.g. during
the entrance into the obstetric canal or in the case of problems
with the umbilical cord, xenon-(oxygen) respiration of the mother
and respiration of the child as soon after the birth as possible,
respectively, can prevent the negative effects of increased
dopamine release during the oxygen deficiency.
[0040] In the case of schizophrenia, patients suffer from periodic
schizophrenia (catatonia), the progress is very sudden, the picture
of the state being characterized by dramatic symptoms which show
varying pictures and are full of delusions and hallucinations.
Often a phase disappears as rapidly as it started. Such phases or
attacks can be triggered spontaneously by stress situations. Rapid
respiration with a xenon gas mixture during the state of stress can
at least reduce the intensity of the attack. For this application,
it is an obvious thing to equip patients with xenon inhalators
which permit self-medication.In this case, it is conceivable to use
containers which, similar to asthma sprays, are filled with xenon
which will be released if a trigger is pressed. The same applies
analogously to the treatment of depressive patients whose moods
change almost daily and who as a result thereof require
state-related medication.
[0041] Chronic Parkinson's disease is accompanied by progressive
symptoms. A consequent xenon treatment reduces the neurotransmitter
release and slows down the progression, or even brings the
progression of the disease to a stand-still. In this case,
intermittent treatment offers itself in which the patient is
respirated with xenon at certain intervals. The same applies to
patients who suffer from the Gilles de la Tourette syndrome. Their
tics also become more and more distinct as the disease
proceeds.
[0042] In the case of acute threatening states, such as a
craniocerebral trauma or an ischemia, respiration can
advantageously be carried out with a xenon-oxygen mixture of 90:10%
by volume, preferably 80:20% by volume, and most preferably
75-70:25-30% by volume, over several hours to one day. As compared
thereto, the intermittent respiration by a xenon-air mixture to
which less xenon has been added, e.g. 5 to 30% xenon, preferably 10
to 20% xenon, can be considered in chronic progressions of a
disease.
[0043] Various methods for the inhalation of xenon and xenon
mixtures, respectively, can be used which depend on the respective
intended use. In clinics, it is possible to use anesthetic
apparatus, in which prefabricated xenon-oxygen mixtures can be
connected to the corresponding inlets of the anesthetic apparatus.
Respiration is then carried out according to a procedure which is
common for such apparatus. The same applies analogously to the
cardio-pulmonary bypass machine.
[0044] As an alternative, xenon can be mixed with ambient air
instead of oxygen in the mobile use, which due to the smaller size
of the required pressure bottles increases the mobility of the
apparatus. For example, it is possible to use an inhalator which
supplies xenon from a pressure bottle and is accommodated in a
support, together with the latter, to a mixing chamber. On one
side, this mixing chamber contains a mouthpiece for inhaling the
xenon, and on the other side on which the xenon is supplied to the
mixing chamber it has at least one additional check valve which
enables the inlet of ambient air. The xenon pressure container can
be equipped with a pressure reducing valve, for example, which
reduces the amount of xenon gas supplied to a suitable value. When
the patient breathes in, he sucks in air from the air valves. In
the mixing chamber, this air is mixed with the supplied xenon to
the desired ratio and then inhaled by the patient. An advantageous
inhalator intended for mobile use and serving for inhaling xenon
and its mixtures is shown in, for example, European Patent No.
560,928.
[0045] In a further simplified embodiment, e.g. for
self-medication, a mouthpiece is connected directly to the xenon
pressure container. During inhalation, the patient opens the
pressure valve and inhales xenon simultaneously with the air from
the environment. When he breathes out, he releases the valve, so
that no more xenon reaches the mouthpiece. In this manner, at least
a coarse regulation of the amount of inhaled xenon is possible.
[0046] The present invention is explained in more detail below,
reference being made to attached FIGS. 1 and 2, which show the
dopamine release in cell cultures exposed to hypoxic shock.
[0047] The function of the present invention shall be explained in
more detail below by means of the following examples.
EXAMPLE 1
[0048] An in vitro experiment with PC12 cells is concerned. These
PC12 cells are dependants of a pheochromocytoma of rats. Here a
catecholamine-producing tumor of the suprarenal cortex is
concerned, which shows permanent dopamine release in a malignant
form. PC12 cells can be reproduced continuously in vitro. Following
the addition of "nerve growth factor", they start differentiating
and become neurons which in many respects have the property of in
vivo neurons, particularly the properties which relate to the
neurotransmitter release. PC12 cells are acknowledged as neuronal
model.
[0049] PC12 cells differentiated in such a manner when exposed to a
hypoxic situation, release dopamine. Such a hypoxic situation is an
artificially induced stress state for the cells, in which e.g. the
oxygen supply is dropped or impeded. If the cells are treated under
these hypoxic conditions with xenon in defined concentrations over
the same period of time, the neurotransmitter release will be
dropped. The time course of such an experiment is shown in FIG. 1
by way of example. The curve of the non-stressed controls,
illustrated by solid squares, shows a low dopamine concentration
throughout the time course, which is subject to certain
fluctuations. If a hypoxic situation is triggered by a dose of
helium instead of oxygen, the curve of the dopamine concentration
will result as shown in the curve produced from the solid
triangles. A maximum dopamine concentration is shown in this case
after about 40 minutes. However, if xenon is given in a hypoxic
situation, the cells will virtually no longer differ from the
control cell population, as shown by the plot illustrated by solid
circles. In connection with the relative dopamine concentration
shown in part B of FIG. 1 it can also be clearly seen that the
dopamine release is reduced down to values of the control cells. In
this connection, it was found that the xenon effect is fully
reversible, so that the cells treated in this way cannot be
distinguished from untreated cells after the xenon is washed out.
In the above-described experiment, the gases used were given to the
cells by mixing them with the growth buffer for the cells. In this
case, saturated gas buffer solutions are involved.
EXAMPLE 2
[0050] The differentiated PC12 cells described in Example 1 were
distributed to various vessels and exposed to differing conditions.
The results are shown in FIG. 2. These conditions are defined as
follows:
1 Control: incubation in normal atmosphere (ambient air) N2:
incubation in nitrogen (N2) for 30 minutes [= hypoxia] Xenon:
incubation in xenon for 30 minutes Glu: addition of 10 M glutamate
for 30 minutes of incubation in a normal atmosphere Glu + N2:
addition of 10 M glutamate for 30 minutes of incubation in N2 Glu +
Xe: addition of 10 M glutamate for 30 minutes of incubation in
xenon.
[0051] A hypoxic condition and an increased release of dopamine
resulted in the cells incubated with nitrogen (group: N2). The
dopamine release may even be increased if, in addition to the
nitrogen atmosphere, glutamate, which represents a neurotransmitter
and has a neurotoxic effect in greater doses, was given as well
(group: Glu+N2). However, if 10 M glutamate was given in the
simultaneous presence of xenon (Group: Glu+Xe), a slightly
increased dopamine release would still result, but which was
nevertheless reduced by two-thirds as compared to the corresponding
(glutamate+N.sub.2) experiment.
[0052] The results shown in FIG. 2 demonstrate that in stress
situations such as hypoxia, the neurotransmitters glutamate and
dopamine are released in large quantities. This results in a)
direct damage to the neighboring neuronal tissues, mainly by
inducing apoptosis and b) indirectly, an additional increased
release of other neurotransmitters. Thus, the addition of glutamate
to the cells effects an increased dopamine release, particularly
when the cells are kept under hypoxic conditions. The unintentional
neurotransmitter release could be reduced many times over by the
simultaneous supply of xenon.
[0053] It can therefore be shown, on an overall basis, that in the
present invention xenon can stop rapidly and without other
permanent side-effects the neurotransmitter release temporarily.
Hence it follows that xenon can be used in defined concentrations
in a therapeutically useful manner in all pathologic conditions
characterized by unregulated neurotransmitter release. The simple
application by inhalation and the harmlessness of xenon render this
therapy especially attractive. Although the invention herein has
been described with reference to particular embodiments, it is to
be understood that these embodiments are merely illustrative of the
principles and applications of the present invention. It is
therefore to be understood that numerous modifications may be made
to the illustrative embodiments and that other arrangements may be
devised without departing from the spirit and scope of the present
invention as defined by the appended claims.
* * * * *