MXPA01009121A - Use of xenon for treating neurointoxications - Google Patents

Abstract

The present invention relates to the use of xenon or xenon gas mixtures for treating neurointoxications. In particular, the present invention is directed to such a xenon use in which the neurointoxication is caused by a neurotransmitter excess. Xenon can reduce the release of neurotransmitters, particularly dopamine, which are caused e.g. by hypoxic situations such as an apoplexy or a craniocerebral trauma. A preparation containing xenon can also be used as therapeutic agent in the case of depressions, schizophrenia and Parkinson's disease, in which the neurotransmitter equilibrium is also disturbed. The application by inhalation is simple and the harmlessness of xenon has already been proved by its use as anesthetic agent.

Description

> USE OF XENON TO TREAT NEUROINTOXICATIONS FIELD OF THE INVENTION The present invention relates to the use of xenon to treat neurointoxications. In particular, the present invention relates to the use of xenon, in which neurointoxication is caused by an excess of neurotransmitter.

BACKGROUND OF THE INVENTION The uncontrolled release of neurotransmitters, particularly glutamate, noradrenaline and dopamine, is responsible for many acute and chronic brain intoxications, which are known as neurointoxications or neuro-poisoning. These neurotransmitters kill the neurons affected either by induction or apoptosis (controlled cell death) and / or secondary oxygen forming radicals, which in turn, have toxic effects a release not Controlling the neurotransmitters that result in a strong increase in the concentration of neurotoxins in the affected tissue may be due to various endogenous or exogenous causes. For example, an increase in the release of glutamate or dopamine can result in an acute craniocerebral trauma.

An increase in neurotransmitter release has also been observed in response to oxygen deficiency in the brain, for example in the case of stroke (ischemia) or in the case of other hypoxia, particularly during the birth of a child. Drug abuse represents another cause of damaged neurotransmitter release. In certain forms of schizophrenia, stress-induced relapses of schizophrenia (acute episodes) are also accompanied by an increase in neurotransmitter release. Finally, a chronic deviation of the neurotransmitter balance has also been observed, particularly in the balance of dopamine, in the regions of the brain in the case of Parkinson's disease. Here also occurs an increase in the release of dopamine and the subsequent formation of free radicals. Several investigations made with cell cultures and experimental animals prove the release of neurotransmitters, particularly as a result of oxygen deficiency. For example, it could be shown that in rats in which the dopamine 6-hydroxy-dopamine neurotoxin was unilaterally infused into the substantia nigra, which resulted in a unilateral depletion of dopamine in the ipsilateral stratum, an ischemia induced experimentally in The region of dopamine depletion led to damage that was less than in other regions of the brain. These results suggest that dopamine plays a part in striatal cell death induced by ischemia (Clemens and Phebus, Life Science, Vol 42, p 707 et seq., 1988). It could also be shown that dopamine is released in large amounts of striatum during cerebral ischemia (Khan et al., Anest.Amalog., Vol.80, p.1116 et seq., 1995). The release of neurotransmitters during cerebral ischemia was investigated in detail and seems to play a key role in excitotoxic neural death. For example, Kondoh et al., Neurosurgery, Vol. 35, p. 278 et seq., 1994, showed that changes in the release and metabolism of the neurotransmitter may reflect changes in cell metabolism during ischemia. The increase in extracellular dopamine concentration in the striatum of experimental animals in which experimental strokes were induced is well documented. The contribution of excess dopamine to neuronal damage can be derived from the ability of dopamine antagonists to obtain protection of neurons in ischemia models (Erling et al., Brain Research, Vol. 606, p.99 et seq., 1993). In a cell culture, dopamine mainly produces striatal neuron apoptosis without damaging the cells by a negative effect on oxidative phosphorylation (the ATP / ADP ratio remained unchanged). Nevertheless, if this effect is combined with minimal inhibition of mitochondrial functions, the neurotoxic effect of dopamine will be significantly increased (McLaughlin et al., Journal of Neurochemistry, Vol 70, p 2406 et seq., 1998). In addition to the direct hypotoxicity on the neurons, the stress induced by the effects of oxygen deficiency, particularly during a birth, an increase in dopamine release which results in a conditioning of the brain negative to the inertgic dopa regulations. This means that even children seem to survive a harmless hypoxic birth phase, have a tendency toward seizures and epileptic conditions when they are larger. Another thing of a disturbed neurotransmitter release is represented by drug abuse. In particular, if drugs such as designed drugs (eg ecstasy, etc.) or heroin are consumed and overdosed amphetamines, people will show signs of intoxication and often spasmophilia, which is based on an increase in neurotransmitter release. . The causes of schizophrenia are also due to complex damage of neurotransmitter regulation. Patients with schizophrenia are often symptomatic for a prolonged period of time but have a tendency towards spontaneous schizophrenia attacks, which are obviously triggered by a tension-induced release of dopamine even in situations of lower stress. Here, one speaks of catatonic schizophrenia. Additional neuropsychiatric diseases based on increased neurotransmitter release are depressions and Gilles de la Tourette syndrome ("tic disease", "impulsive tics"). Finally, a cause of Parkinson's disease seems to be today in the modulation of dopamine and in the metabolism of dopamine. In Parkinson's disease, the dopaminergic neurons in the striatum are especially damaged. There are references to the effect that Parkinson's disease is caused by an excess of dopamine in the affected region of the posterolateral hypothalamus and the substantia nigra. In this region there are many neurons, which have lost their functionality but not their vitality. These neurons are known as "orphan neurons" that continuously release amounts of neurotransmitter that have pathological effects.

BRIEF DESCRIPTION OF THE INVENTION With the exception of Parkinson's disease where dopa precursors are used as preparations and basically for schizophrenia, there are no therapeutic methods yet that focus on reducing the concentration of dopamine in the environment of the cells in danger. Therefore, there is a demand for a preparation that reduces or prevents the damaging effect of uncontrolled neurotransmitter release, for example, of dopamine, glutamate or noradrenaline, from neurons. The object of the present invention is to provide a preparation that can be used in the aforementioned fields of application and in additional fields. This object is achieved by the subject matter defined in the independent claims 1, 15 and 17. The additional advantageous embodiments and aspects of the present invention come from the dependent claims, the description and the attached drawings. It has surprisingly been found that noble xenon gas reversibly suppresses the release of neurotransmitters, particularly dopamine and glutamate. This unexpected discovery would result in the possibility of producing preparations for treating cellular damage and diseases, respectively, which are caused by an increase in neurotransmitter release, particularly the release of dopamine or the release of glutamate. Correspondingly, the present invention is generally focused on the use of xenon to treat neurointoxications and on the production of a preparation containing xenon to treat neurointoxications, respectively. The invention also relates to the preparation as such and to a method for producing the same. Such neurointoxications are particularly related to an excess of neurotransmitter. The invention is based particularly on the fact that xenon reduces the release of dopamine and / or glutamate. According to the invention, it is understood that the neurointoxications of the invention mean the chronic "acute state of poisoning" of the CNS (Central Nervous System), particularly of the brain, which in most cases result in symptoms of severe deficiency of the affected areas. These states of poisoning result from an excess of neurotransmitter, particularly glutamate, noradrenaline and / or dopamine, which may be due to a variety of causes. The aforementioned diseases, such as stroke, hypoxia, oxygen deficiency during birth, Parkinson's disease, craniocerebral trauma, drug abuse, schizophrenia, depression and Gilles de la Tourette syndrome have been mentioned here. The inventors also found that patients who must be connected to a cardiovascular diversion machine often suffer from symptoms of cerebral deficiency, which are due to an excess of neurotransmitter caused by hypoxia. For example, that the use of the cardiopulmonary bypass machine can cause an often unidentified neuroidentification that delays patient convalescence considerably. It was also found that any prolonged artificial expiration can result in undesirable neurointoxication as a side effect. In recent research conducted by the inventors, the surprising idea arose that the loss of the ear (for example due to noise, presbycusis, tinnitus, sudden deafness) can also be caused by a neurointoxication. The excess release of the neurotransmitter, particularly the excessive release of glutamate and dopamine, which may have been caused for example in the body, an acoustic trauma or ischemia, results in an acute destruction of the nerve terminals and subsequently the death of the corresponding nerves in the organs of the ear. Migraine has been considered another disease that is most likely due to a damaged balance of dopamine and in this way to a neurointoxication. The discovery that the release of neurotransmitter can be influenced by xenon allows a completely new field of application for this noble gas, which has been increasingly used as an anesthetic agent by inhalation in the field of anesthesia. The treatment of the various neurotransmitter excess diseases mentioned above and others of the brain can be carried out on the basis of the present invention by means of a simple inhalation therapy. The absorption of xenon via the respiratory system and transport to the brain is already proven by its use as an anesthetic agent. It can also be assumed that the use of xenon has no harmful effect on the human organism, since many corresponding experiences could already be assumed by its use as an anesthetic agent. Xenon can be applied by several techniques, which can be chosen as a function of the place of use. For example, an inhalation device can be used in clinics, which are also used for inhalation anesthesia. If a cardiopulmonary bypass machine or other artificial respiration device is used, xenon can be added directly to the machine and does not require an additional device. Here, the addition of standard xenon can prevent the formation of neurointoxications in the model case (prophylaxis) or reduce the deficiency symptoms less. On a mobile basis, for example in the primary treatment of victims of an accident, it is possible to use simpler inhalers, which mix the xenon with the ambient air during the inhalation process. In relation to this, it is also possible to adapt the xenon concentration and the time of use of the xenon in a simple way 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 and other gases without danger to humans.

In patients suffering from severe craniocerebral trauma, breathing 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 that accompany this trauma. In such accidents, the additional lateral anesthetic effect is desirable, since the patient can be relieved of pain by it. An essential feature of acute ischemia in the brain is represented by the secondary neurotoxic effects that are formed due to the increased release of neurotransmitter and are responsible for the death of neurons in the ischemic marginal region. Although an immediate treatment with xenon, for example even by the emergency physician who carries out the initial treatment in the case of a stroke patient, can not prevent ischemia per se, can at least reduce it, or even prevent neurotoxicity due to the neurotransmitters released in second place. -In this way, the permanent damage that often occurs in this case of stroke can be reduced. The same applies analogously to measures which would have to be taken if symptoms of disease occur after drug abuse and loss of hearing or a migraine attack. In the case of oxygen deficiency during a birth, for example during the entrance to the obstetric canal or in the case of problems with the umbilical cord, respiration with xenon (oxygen) from the mother and the child's breathing as soon as possible Possible after birth, respectively, can prevent the negative effects of increased dopamine release during oxygen deficiency. In the case of patients with schizophrenia who suffer from periodic schizophrenia (catatonia), the progress is very sudden, the state picture is characterized by dramatic symptoms which show variable characteristics and are full of delusions and hallucinations. Often a phase disappears as quickly as it started. Such phases or attack can be triggered spontaneously by stress situations. Rapid breathing with a mixture of xenon gas during the state of tension can at least reduce the intensity of the attack. For such an application it is obvious to equip patients with xenon inhalers that allow them to self-medicate. Here, it is considerable to use containers which - similarly to the casts for asthma - are filled with xenon, which will be released if a trigger is pressed. The same applies analogously to the treatment of depressive patients whose behavior changes almost daily and who, as a result, require a medication related to the condition. Chronic Parkinson's disease is accompanied by progressive symptoms. Consequently a treatment with xenon reduces the release of the neurotransmitter and slows the progress or even leads the progress of the disease to stagnation. In this case, this offers intermittent treatment in which the patient breathes xenon at certain intervals. The same applies to patients suffering from Gilles de la Tourette syndrome. Your tics also become more and more distant as the disease proceeds. In the case of acute threatening states, such as a craniocerebral trauma or ischemia, respiration can be advantageously carried out with a 90: 10% by volume xenon-oxygen mixture, preferably 80: 20% by volume. volume, more preferably 75-70: 25-30% by volume, for several hours to one day. In comparison with this, intermittent breathing by a mixture of xenon-air to which less xenon is added, for example from 5 to 30% of xenon, preferably from 10 to 20% of xenon, can be considered in the chronic progress of a disease. Various methods can be used for the inhalation of xenon and xenon samples respectively, which depends on the respective intended use. In clinics, it is possible to use anesthesia devices, in which prefabricated xenon-oxygen mixtures can be connected to the corresponding entrances to the anesthesia device. The breathing is carried out according to a common procedure for such an apparatus. The same applies analogously to cardiopulmonary bypass machines. As an alternative, xenon can be mixed with ambient air instead of oxygen in mobile use, which is because the smaller size of the pressure bottles required increases the mobility of the device. For example, it is possible to use an inhaler that supplies xenon from a pressure bottle and that is accommodated in a holder together with the latter, or a mixing chamber. On one side this mixing chamber contains a nozzle for inhaling the xenon and on the other side on which the xenon is supplied to the mixing chamber, this has at least one additional check valve, which allows air to enter. environmental. The xenon pressure vessel can be applied with a pressure reducing valve, for example, which reduces the amount of xenon gas supplied to a suitable valve. When the patient breathes, suck air from the air valves. In the mixing chamber, this air is mixed with the xenon supplied to the desired ratio and then inhaled by the patient. An advantageous inhaler intended for mobile use and for servicing for inhaling xenon and its mixtures is shown in EP-B-0 560 928, for example. In a further simplified embodiment, for example for self-medication, a nozzle is directly connected to the pressure vessel of xenon. During inhalation the patient opens the pressure valve and inhales xenon simultaneously with ambient air. When he exhales, he releases the valve, so that no more xenon reaches the nozzle. In this way, at least an approximate regulation of the amount of the inhaled xenon is possible.

BRIEF DESCRIPTION OF THE FIGURES The invention is explained in more detail below, with reference to the attached figures 1 and 2, which show the release of dopamine in cell cultures exposed to epoxide shock.

DETAILED DESCRIPTION OF THE INVENTION The function of the invention will be explained later by means of the following examples.

Example 1 An in vi tro experiment was carried out with PC12 cells. Those PC12 cells are dependent on a pheochromocytoma of rats. Here we used a catecholamine-producing tumor of the adrenal cortex, which shows permanent dopamine release in a malignant form. PC12 cells can reproduce continuously in vi tro. After the addition of "nerve growth factor", they begin to differentiate and become neurons which in many ways have the property of the neurons in vivo, particularly the properties that are related to the release of the neurotransmitter. PC12 cells are recognized as a neuronal model. PC12 cells differentiate in such a way when they are exposed to a hypoxic situation after which they release dopamine. Such a hypoxic situation is a state of tension induced artificially by the cells, in which for example the supply of oxygen falls or is prevented. If the cells are treated under these hypoxic conditions with xenon and defined concentrations during the same period of time, the neurotransmitter release will fall. The time course of such an experiment is shown in Figure 1, by way of example. The curve of the unstressed controls, illustrated by solid frames, shows a low concentration of dopamine through the time course, which is subject to certain fluctuations. If a hypoxic situation is triggered by the dosage of helium instead of oxygen, the curve of concentration of dopamine shown in the curve with the solid triangles will result. A maximum dopamine concentration is demonstrated here after about 40 minutes. However, if xenon is provided in a hypoxic situation, the cells will virtually no longer be differentiated from the control cell population as shown by the graph illustrated by solid circles. In relation to the concentration of dopamine shown in part B of Figure 1, it can also be clearly seen that the release of dopamine was reduced below the values of the control cells. In this regard, it was found that the effect of xenon is completely reversible, so that cells treated in this way can not be distinguished from untreated cells after the xenon is washed. In the experiment described above, the gases used were provided to the cells by mixing them with growth buffer for the cells. Here, buffer solutions saturated with gas were used.

Example 2 The differentiated PC12 cells described in Example 1 were distributed to various containers and exposed to different conditions. The results are shown in Figure 2. 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 μM glutamate for 30 minutes of incubation in a normal atmosphere. Glu + N2: addition of 10 μM glutamate for 30 minutes of incubation in N2. Glu + Xe: addition of 10 μM glutamate for 30 minutes of incubation in xenon. A condition of hypoxia and an increase in dopamine release was the result of cells incubated with nitrogen (group: N2). The release of dopamine could be increased even if, in addition to the nitrogen atmosphere, glutamate, which represents a neurotransmitter and has a neurotoxic effect, has also been provided in larger doses (group: Glu + N2). However, if 10 μM glutamate was provided in the simultaneous presence of xenon (Group: Glu + Xe), resulting in a slightly increased release of dopamine but this was reduced by two thirds compared to the corresponding experiment (glutamate + N2). The results shown in Figure 2 establish that in stress situations such as hypoxia, the neurotransmitters glutamate and dopamine are released in large quantities. This results in a) direct damage to neighboring neuronal tissues, mainly by the induction of apoptosis and b) indirectly, an additional increase in the release of other neurotransmitters. Thus, the addition of glutamate to the cells effects an increase in dopamine release, particularly when the cells were maintained under hypoxic conditions. The unintentional release of neurotransmitter could be reduced many times by the simultaneous supply of xenon. It could be fully demonstrated in the present invention that the xenon could stop rapidly and without other permanent side effects temporarily the neurotransmitter release. Consequently, it turns out that xenon can be used in defined concentrations in a therapeutically useful form in all pathological conditions characterized by an unregulated neurotransmitter release. The simple application by inhalation and the absence of danger of xenon make this therapy especially attractive. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as proper: 1. The use of xenon or mixtures of xenon gas to treat neurointoxications.
2. 2. The use according to claim 1, characterized in that the neurointoxication is caused by an excess of neurotransmitter.
3. 3. The use according to claim 1, characterized in that the xenon reduces the release of dopamine, glutamate and / or noradrenaline.
4. 4. The use according to any of claims 1 to 3, characterized in that the neurointoxication is caused by a stroke.
5. 5. The use according to any of claims 1 to 3, characterized in that the neurointoxication is caused by the abuse of drugs.
6. 6. The use according to any of claims 1 to 3, characterized in that the neurointoxication is caused by oxygen deficiency during birth.
7. 7. The use according to any of claims 1 to 3, characterized in that the neurointoxication is correlated with Parkinson's disease, schizophrenia or Gilles de la Tourette syndrome.
8. 8. The use according to any of claims 1 to 3, characterized in that the neurointoxication is caused by a craniocerebral trauma.
9. The use according to any of claims 1 to 3, characterized in that xenon is used in a mixture of xenon gas in a cardiopulmonary bypass machine.
10. 10. The use according to any of claims 1 to 3, characterized in that the neurointoxication causes the loss of the ear.
11. 11. The use according to any of claims 1 to 3, characterized in that the neurointoxication is caused by migraine.
12. 12. The use according to any of claims 1 to 10, characterized in that a preparation administered for therapy contains from 5 to 90% by volume of oxygen.
13. 13. The use according to claim 12, characterized in that the preparation contains from 5 to 30% by volume of xenon.
14. The use according to any of claims 1 to 3, characterized in that a preparation administered for therapy also contains oxygen and / or nitrogen and / or air.
15. 15. The use according to claim 12, characterized in that the preparation has a ratio of xenon to oxygen of 80 to 20% by volume.
16. 16. A preparation, characterized in that it contains xenon or a mixture of xenon gas to treat neurointoxications.
17. 17. The preparation according to claim 13, characterized in that it contains xenon and a gas containing xenon.
18. 18. A method to produce an inhalable preparation characterized by mixing xenon with another gas not dangerous to humans.
19. 19. The method according to claim 18, characterized in that the xenon is mixed with an oxygen-containing gas.