US20030180375A1 - Use of xenon for treating neurointoxications - Google Patents
Use of xenon for treating neurointoxications Download PDFInfo
- Publication number
- US20030180375A1 US20030180375A1 US10/342,968 US34296803A US2003180375A1 US 20030180375 A1 US20030180375 A1 US 20030180375A1 US 34296803 A US34296803 A US 34296803A US 2003180375 A1 US2003180375 A1 US 2003180375A1
- Authority
- US
- United States
- Prior art keywords
- xenon
- dopamine
- release
- mammal
- treating
- 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.)
- Abandoned
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- 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.
- neurotransmitters particularly glutamate, noradrenalin and dopamine
- neurointoxications 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.
- stress-induced relapses back into schizophrenia are also accompanied by increased neurotransmitter release.
- 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.
- 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).
- Another cause of a disturbed neurotransmitter release is represented by drug abuse.
- 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.
- Parkinson's disease is presently believed to be in dopamine modulation and in dopamine metabolism.
- 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.
- a method for treating a mammal for neurointoxication comprising treating the mammal with a xenon-containing gas.
- the xenon-containing gas comprises a mixture of gases.
- the neurointoxication is caused by an excess of neurotransmitter in the mammal.
- treating of the mammal with the xenon-containing gas comprises reducing the release of neurotransmitters in the mammal.
- the neurotransmitters are dopamine, glutamate and/or noradrenalin.
- the neurointoxication is caused by apoplexy.
- the neurointoxication is caused by drug abuse, oxygen deficiency during birth, a craniocerebral trauma, loss of hearing, or migraine.
- the neurointoxication is correlated with a condition such as Parkinson's disease, schizophrenia, or Gilles de la Tourette syndrome.
- the treating of the mammal with the xenon-containing gas comprises using a cardio-pulmonary bypass machine.
- the xenon-containing gas comprises an administered preparation containing from 5 to 90% by volume of the xenon.
- the xenon-containing gas comprises an administered preparation containing from 5 to 30% by volume of the xenon.
- the xenon-containing gas comprises an administered preparation containing a gas such as oxygen, nitrogen or air.
- a gas such as oxygen, nitrogen or air.
- the xenon-containing gas comprises oxygen, and the ratio of the xenon to the oxygen is from about 80 to 20% by volume.
- a treatment method comprising using xenon as a neuroprotectant.
- a method of providing neuroprotection in a mammal comprising administering to the mammal a therapeutically effective amount of xenon.
- the method includes administering the xenon in combination with a compound such as a pharmaceutically acceptable carrier, diluent and/or excipient.
- the method includes treating the mammal for a condition associated with NMDA receptor activity.
- the method includes treating the mammal for a condition associated with NMDA receptor activation.
- the xenon reduces the level of activation of the NMDA receptor.
- a process 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.
- 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.
- 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.
- FIG. 1A is a graphical representation of the release of dopamine under various hypoxic situations
- FIG. 1B is a graphical representation of relative dopamine concentration as a result of various hypoxic situations.
- FIG. 2 is a graphical representation showing release of dopamine in various stress situations.
- 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.
- CNS central nervous system
- neurotransmitter particularly of glutamate, noradrenalin and/or dopamine
- 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 hearing loss e.g. due to noise, presbycusis, tinnitus, or sudden deafness
- 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.
- Xenon can be applied by various techniques, which can be chosen as a function of the location of use.
- inhaling apparatus can be used in the clinics, which are also used for anesthesia by inhalation.
- 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.
- standard xenon addition can prevent the formation of neurointoxications in the model case (prophylaxis) or at least reduce the deficiency symptoms.
- respiration with a xenon-oxygen mixture can prevent, or at least reduce, the release of dopamine and thus the secondary neurotoxic effects accompanying this trauma.
- the additional anesthetic side-effect is desired, since the patient can be freed from pain thereby.
- 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.
- 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.
- the permanent damage frequently occurring in the case of apoplexy can be reduced.
- measures which will have to be taken if disease symptoms occur after drug abuse and loss of hearing, or a migraine attack are analogously to measures which will have to be taken if disease symptoms occur after drug abuse and loss of hearing, or a migraine attack.
- 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.
- 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.
- 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.
- 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.
- 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.
- an inhalator which supplies xenon from a pressure bottle and is accommodated in a support, together with the latter, to a mixing chamber.
- 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.
- a mouthpiece is connected directly to the xenon pressure container.
- the patient opens the pressure valve and inhales xenon simultaneously with the air from the environment.
- 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.
- FIGS. 1 and 2 show the dopamine release in cell cultures exposed to hypoxic shock.
- PC12 cells are dependants of a pheochromocytoma of rats.
- 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.
- PC12 cells differentiated in such a manner when exposed to a hypoxic situation, release dopamine.
- 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.
- 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).
- group: Glu+N2 glutamate
- 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 2 ) experiment.
- FIG. 2 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.
- 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.
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Inorganic Chemistry (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Heart & Thoracic Surgery (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Psychology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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.
Description
- This is a divisional of U.S. patent application Ser. No. 09/936,319, filed on Dec. 19, 2001.
- 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.
- 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.
- 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).
- 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).
- 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.
- 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).
- 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.
- 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.
- 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”).
- 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.
- 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.
- 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.
- 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.
- In accordance with one embodiment of the method of the present invention, the neurointoxication is caused by an excess of neurotransmitter in the mammal.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- In accordance with another aspect of the present invention, a treatment method has been discovered comprising using xenon as a neuroprotectant.
- 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.
- 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.
- 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.
- In accordance with another embodiment of this method of the present invention, the xenon reduces the level of activation of the NMDA receptor.
- 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.
- 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.
- 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.
- The present invention may be more fully appreciated with reference to the following detailed description, which, in turn, refers to the Figures wherein:
- FIG. 1A is a graphical representation of the release of dopamine under various hypoxic situations;
- FIG. 1B is a graphical representation of relative dopamine concentration as a result of various hypoxic situations; and
- FIG. 2 is a graphical representation showing release of dopamine in various stress situations.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- The function of the present invention shall be explained in more detail below by means of the following examples.
- 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.
- 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.
- 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:
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. - 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+N2) experiment.
- 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.
- 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.
Claims (7)
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.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/342,968 US20030180375A1 (en) | 1999-03-11 | 2003-01-15 | Use of xenon for treating neurointoxications |
US11/650,211 US8143317B2 (en) | 1999-03-11 | 2007-01-04 | Use of xenon for treating neurointoxications |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19910986A DE19910986C2 (en) | 1999-03-11 | 1999-03-11 | Use of xenon in the treatment of neurointoxication |
DE19910986.9 | 1999-03-11 | ||
US09/936,319 US6559190B1 (en) | 1999-03-11 | 2000-03-08 | Use of xenon for treating neurointoxications |
US10/342,968 US20030180375A1 (en) | 1999-03-11 | 2003-01-15 | Use of xenon for treating neurointoxications |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/936,319 Division US6559190B1 (en) | 1999-03-11 | 2000-03-08 | Use of xenon for treating neurointoxications |
PCT/EP2000/002025 Division WO2000053192A1 (en) | 1999-03-11 | 2000-03-08 | Use of xenon for treating neurointoxications |
US09936319 Division | 2000-03-08 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/650,211 Continuation US8143317B2 (en) | 1999-03-11 | 2007-01-04 | Use of xenon for treating neurointoxications |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030180375A1 true US20030180375A1 (en) | 2003-09-25 |
Family
ID=7900688
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/936,319 Expired - Lifetime US6559190B1 (en) | 1999-03-11 | 2000-03-08 | Use of xenon for treating neurointoxications |
US10/342,968 Abandoned US20030180375A1 (en) | 1999-03-11 | 2003-01-15 | Use of xenon for treating neurointoxications |
US11/650,211 Expired - Fee Related US8143317B2 (en) | 1999-03-11 | 2007-01-04 | Use of xenon for treating neurointoxications |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/936,319 Expired - Lifetime US6559190B1 (en) | 1999-03-11 | 2000-03-08 | Use of xenon for treating neurointoxications |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/650,211 Expired - Fee Related US8143317B2 (en) | 1999-03-11 | 2007-01-04 | Use of xenon for treating neurointoxications |
Country Status (29)
Country | Link |
---|---|
US (3) | US6559190B1 (en) |
EP (1) | EP1158992B2 (en) |
JP (1) | JP4954373B2 (en) |
KR (1) | KR100674407B1 (en) |
CN (1) | CN1170544C (en) |
AR (1) | AR022886A1 (en) |
AT (1) | ATE248599T1 (en) |
AU (1) | AU757361B2 (en) |
BG (1) | BG105889A (en) |
BR (1) | BR0010456A (en) |
CA (1) | CA2367136C (en) |
CZ (1) | CZ302864B6 (en) |
DE (2) | DE19910986C2 (en) |
DK (1) | DK1158992T3 (en) |
EE (1) | EE200100480A (en) |
ES (1) | ES2206202T5 (en) |
HK (1) | HK1048073B (en) |
HU (1) | HUP0201393A3 (en) |
IL (2) | IL145177A0 (en) |
MD (1) | MD2935C2 (en) |
NO (1) | NO20014379L (en) |
PL (1) | PL202941B1 (en) |
PT (1) | PT1158992E (en) |
RS (1) | RS49756B (en) |
RU (1) | RU2246949C2 (en) |
SI (1) | SI1158992T1 (en) |
SK (1) | SK285111B6 (en) |
WO (1) | WO2000053192A1 (en) |
ZA (1) | ZA200107291B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006017524A3 (en) * | 2004-08-02 | 2006-08-31 | John W Olney | Preventing pathological increases in the rate of nerve cell suicide in immature nervous systems |
WO2007075100A1 (en) * | 2005-12-27 | 2007-07-05 | Zakrytoe Aktsionernoe Obshchestvo 'atom-Med Center' | Method for treating drug dependence |
US10369103B2 (en) | 2012-08-10 | 2019-08-06 | The Board Of Regents Of The University Of Texas System | Neuroprotective liposome compositions and methods for treatment of stroke |
US11491184B2 (en) | 2013-03-15 | 2022-11-08 | The Board Of Regents Of The University Of Texas System | Liquids rich in noble gas and methods of their preparation and use |
Families Citing this family (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9913677D0 (en) | 1999-06-11 | 1999-08-11 | Imperial College | Formulation |
US6653354B2 (en) | 1999-07-29 | 2003-11-25 | Protexeon Limited | NMDA antagonist comprising xenon |
GB9917822D0 (en) * | 1999-07-29 | 1999-09-29 | Imperial College | Nmda antagonist |
DE10045829A1 (en) * | 2000-09-14 | 2002-04-04 | Messer Griesheim Gmbh | Volatile anesthetic with xenon |
DE10054563A1 (en) * | 2000-11-03 | 2002-05-16 | Messer Griesheim Gmbh | Method and device for making concrete |
WO2002045583A1 (en) * | 2000-12-07 | 2002-06-13 | Mclean Hospital Corporation | Use of magnetic resonance imaging in diagnosis of membrane fluidity-related disorders |
GB0210021D0 (en) | 2002-05-01 | 2002-06-12 | Air Prod & Chem | Ultrasonic gas analyser |
GB0209998D0 (en) | 2002-05-01 | 2002-06-12 | Protexeon Ltd | Use |
WO2003105871A1 (en) * | 2002-06-12 | 2003-12-24 | Messer Griesheim Gmbh | Cerebral protection with a gas comprising xenon |
US20050255169A1 (en) * | 2002-07-05 | 2005-11-17 | Messer Griesheim | Adjuvant containing xenon |
GB0218153D0 (en) * | 2002-08-05 | 2002-09-11 | Ic Innovations Ltd | An analgesic agent for newborn or retal subjects |
US7337776B2 (en) | 2002-08-20 | 2008-03-04 | Aga Ab | Methods for easing pain and anxiety from atrial or ventricular defibrillation |
US7681572B2 (en) | 2002-08-20 | 2010-03-23 | Aga Ab | Method and devices for administration of therapeutic gases |
FR2858233B1 (en) * | 2003-07-30 | 2008-04-11 | Air Liquide Sante Int | INHALABLE GAS MEDICINE BASED ON XENON AND NITROGEN PROTOXIDE |
JP4880466B2 (en) * | 2003-10-10 | 2012-02-22 | プロテクソン リミテッド | Use of xenon in hypothermia to treat neonatal asphyxia |
CA2542412A1 (en) * | 2003-10-21 | 2005-05-06 | Aga Ab | Use of xenon for the prevention of programmed cell death |
FR2863169B1 (en) | 2003-12-08 | 2006-02-10 | Air Liquide Sante Int | ARGON-BASED INHALABLE GAS MEDICINE FOR THE TREATMENT OF NEURO-INTOXICATIONS |
EP1552840A1 (en) * | 2004-01-07 | 2005-07-13 | Aga Ab | Use of a xenon/carbon monoxide mixture for the protection of cells |
US7070005B2 (en) * | 2004-02-10 | 2006-07-04 | Planetair Turf Products, Llc | Soil aerator assembly |
EP1980260A1 (en) * | 2007-04-10 | 2008-10-15 | Nicholas Peter Franks | Use of hyperbaric conditions to provide neuroprotection |
WO2008132239A1 (en) * | 2007-04-30 | 2008-11-06 | Nnoxe Pharmaceutiques Inc | Pharmaceutical composition comprising at least one thrombolytic agent (a) and at least one gas (b) selected from the group consisting of nitrous oxide, argon, xenon, helium, neon |
ITMI20071031A1 (en) * | 2007-05-22 | 2008-11-23 | Acetilene & Deriv Ati Siad Spa | USE OF XENON FOR THE PROTECTION OF DAMAGED DAMAGE ORGANS |
WO2010035074A1 (en) * | 2008-09-25 | 2010-04-01 | Nnoxe Pharmaceutiques Inc | Use of nitrous oxide, argon, xenon, helium, or neon, for the manufacture of a pharmaceutical composition for treating ischemic insults in patients who cannot be treated with thrombolytic agents |
FR2952305B1 (en) * | 2009-11-10 | 2012-04-27 | Air Liquide | XENON-BASED INHALABLE MEDICINE FOR TREATING OR PREVENTING DYSKINESIES |
WO2011081612A1 (en) * | 2009-12-31 | 2011-07-07 | Bondarenko Vitaliy Leonidovich | Use of krypton or xenon as an antiviral agent |
FR2956323B1 (en) | 2010-02-15 | 2013-12-20 | Air Liquide | ARGON-BASED INHALABLE GAS MEDICINE AGAINST PERIPHERAL ORGAN DEFECTS OR MALFUNCTIONS |
FR2960779A1 (en) | 2010-06-08 | 2011-12-09 | Air Liquide | INHALABLE GASEOUS MEDICINE BASED ON KRYPTON AGAINST PERIPHERAL ORGAN DEFECTS OR FAILURES |
FR2964036B1 (en) | 2010-08-24 | 2013-04-12 | Air Liquide | INHALABLE GASEOUS MEDICINE BASED ON KRYPTON FOR THE TREATMENT OF NEURO-INTOXICATIONS |
EP2672812A4 (en) * | 2011-02-07 | 2014-09-03 | Advanced Preservations Technologies Llc | Method for preserving cells and cell cultures |
FR2975597B1 (en) * | 2011-05-24 | 2013-12-27 | Air Liquide | USE OF NEON FOR THE TREATMENT OF NEURO-INTOXICATIONS, IN PARTICULAR ENURODEGENERATIVE AND DEMYELINISANT DISEASES |
EP2760991B1 (en) | 2011-09-26 | 2017-12-13 | Rich Technologies Holding Company, LLC | Method for living tissue preservation |
RU2489154C1 (en) * | 2012-05-31 | 2013-08-10 | Сергей Александрович Наумов | Method of treating viral hepatites |
FR2996458B1 (en) * | 2012-10-09 | 2015-02-27 | Air Liquide | USE OF XENON TO PREVENT OR TREAT THE NEUROLOGICAL CONSEQUENCES OF A SEPTIC SHOCK |
FR2996457B1 (en) | 2012-10-09 | 2019-11-29 | L'air Liquide,Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | USE OF ARGON TO PREVENT OR TREAT THE NEUROLOGICAL CONSEQUENCES OF A SEPTIC SHOCK |
FR2996459B1 (en) * | 2012-10-09 | 2015-02-06 | Air Liquide | USE OF AN ARGON / XENON MIXTURE TO PREVENT OR TREAT THE NEUROLOGICAL CONSEQUENCES OF A SEPTIC SHOCK |
WO2014093277A1 (en) | 2012-12-11 | 2014-06-19 | The Mclean Hospital Corporation | Xenon and/or argon treatment as an adjunct to psychotherapy for psychiatric disorders |
FR3007983B1 (en) * | 2013-07-08 | 2015-06-26 | Air Liquide | ASSOCIATION OF XENON AND AN NMDA RECEPTOR ANTAGONIST TO FIGHT NEURODEGENERATIVE DISEASE |
FR3022456B1 (en) * | 2014-06-20 | 2016-07-15 | Air Liquide | XENON ASSOCIATED WITH ANTAGONIST OF NMDA RECEPTORS TO FIGHT TUMOR PROLIFERATION IN THE CENTRAL NERVOUS SYSTEM |
FR3027226B1 (en) * | 2014-10-17 | 2017-12-08 | L'air Liquide Sa Pour L'etude Et L'exploitation Des Procedes Georges Claude | MEDICAMENT FOR TREATING A DISEASE RELATED TO A DYSFUNCTION OF THE DOPAMINERGIC SYNAPTIC TRANSMISSION |
EP3313384A4 (en) | 2015-06-23 | 2019-04-03 | Nobilis Therapeutics, Inc. | Therapeutic immune modulation using noble gas compositions |
JP2019501119A (en) * | 2015-11-09 | 2019-01-17 | ザ マクレーン ホスピタル コーポレーション | Methods and compositions for preventing suicide, murder, and self-injurious behavior |
US20170341980A1 (en) * | 2016-05-31 | 2017-11-30 | Noblis Therapeutics, Inc. | Noble gas neuroprotection and neuroregeneration from treatment related neurotoxicity |
US10485825B2 (en) * | 2016-08-29 | 2019-11-26 | Nobilis Therapeutics, Inc. | Prevention of pregnancy complications by noble gas administration |
WO2018081821A1 (en) * | 2016-10-31 | 2018-05-03 | Nobilis Therapeutics, Inc. | Treatment of anxiety disorder and augmentation of anti-anxiety interventions by administration of noble gas containing mixtures |
CN107569509B (en) * | 2017-02-22 | 2018-09-21 | 滨州医学院 | The purposes of xenon or xenon-133 gas mixture in the preparation for preparing treatment epilepsy |
CN108986622A (en) * | 2018-08-16 | 2018-12-11 | 广州迈普再生医学科技股份有限公司 | A kind of intracranial hematoma microtrauma puncture removes art training device and preparation method thereof |
RU2712804C1 (en) * | 2018-08-29 | 2020-01-31 | Жовнерчук Инна Юрьевна | Method for correction of human functional state in confined space |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5228434A (en) * | 1991-07-16 | 1993-07-20 | Praxair Technology, Inc. | Mixture for anesthesia |
US6274633B1 (en) * | 1999-07-29 | 2001-08-14 | Imperial College Of Science, Technology, And Medicine | NMDA antagonist |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5099834A (en) * | 1991-07-16 | 1992-03-31 | Union Carbide Industrial Gases Technology Corporation | Method for anesthesia |
US5357959A (en) * | 1993-04-16 | 1994-10-25 | Praxair Technology, Inc. | Altered dipole moment magnetic resonance imaging method |
US5846556A (en) * | 1996-06-14 | 1998-12-08 | Brooks; Bradley S. | Inhalant for reducing stress and method of use |
IT1286058B1 (en) * | 1996-10-29 | 1998-07-07 | Siad Societa Italiana Acetilen | PROCEDURE AND EQUIPMENT FOR THE PURIFICATION AND RECOVERY OF XENON AND OTHER NOBLE GASES IN ANESTHETICS SYSTEMS |
DE19709704C2 (en) | 1997-03-10 | 1999-11-04 | Michael Georgieff | Use of a liquid preparation of xenon for intravenous administration when inducing and / or maintaining anesthesia |
DE19823606C2 (en) * | 1998-05-27 | 2002-02-28 | Draeger Medical Ag | Use of perfluorocarbons in a breathing gas mixture as well as the device |
-
1999
- 1999-03-11 DE DE19910986A patent/DE19910986C2/en not_active Expired - Lifetime
-
2000
- 2000-03-08 KR KR1020017011477A patent/KR100674407B1/en not_active IP Right Cessation
- 2000-03-08 PL PL350618A patent/PL202941B1/en unknown
- 2000-03-08 EE EEP200100480A patent/EE200100480A/en unknown
- 2000-03-08 CA CA002367136A patent/CA2367136C/en not_active Expired - Fee Related
- 2000-03-08 PT PT00910789T patent/PT1158992E/en unknown
- 2000-03-08 SK SK1279-2001A patent/SK285111B6/en unknown
- 2000-03-08 RS YUP-654/01A patent/RS49756B/en unknown
- 2000-03-08 AT AT00910789T patent/ATE248599T1/en not_active IP Right Cessation
- 2000-03-08 CN CNB008048924A patent/CN1170544C/en not_active Expired - Lifetime
- 2000-03-08 BR BR0010456-6A patent/BR0010456A/en not_active Application Discontinuation
- 2000-03-08 MD MDA20010349A patent/MD2935C2/en not_active IP Right Cessation
- 2000-03-08 CZ CZ20013234A patent/CZ302864B6/en not_active IP Right Cessation
- 2000-03-08 US US09/936,319 patent/US6559190B1/en not_active Expired - Lifetime
- 2000-03-08 RU RU2001126525/14A patent/RU2246949C2/en not_active IP Right Cessation
- 2000-03-08 AU AU32875/00A patent/AU757361B2/en not_active Ceased
- 2000-03-08 DE DE60004974T patent/DE60004974T3/en not_active Expired - Lifetime
- 2000-03-08 JP JP2000603681A patent/JP4954373B2/en not_active Expired - Fee Related
- 2000-03-08 WO PCT/EP2000/002025 patent/WO2000053192A1/en active IP Right Grant
- 2000-03-08 IL IL14517700A patent/IL145177A0/en active IP Right Grant
- 2000-03-08 SI SI200030258T patent/SI1158992T1/en unknown
- 2000-03-08 DK DK00910789T patent/DK1158992T3/en active
- 2000-03-08 HU HU0201393A patent/HUP0201393A3/en unknown
- 2000-03-08 EP EP00910789A patent/EP1158992B2/en not_active Expired - Lifetime
- 2000-03-08 ES ES00910789T patent/ES2206202T5/en not_active Expired - Lifetime
- 2000-03-09 AR ARP000101053A patent/AR022886A1/en not_active Application Discontinuation
-
2001
- 2001-08-29 IL IL145177A patent/IL145177A/en unknown
- 2001-09-03 ZA ZA200107291A patent/ZA200107291B/en unknown
- 2001-09-10 NO NO20014379A patent/NO20014379L/en not_active Application Discontinuation
- 2001-09-11 BG BG105889A patent/BG105889A/en unknown
-
2003
- 2003-01-14 HK HK03100325.3A patent/HK1048073B/en not_active IP Right Cessation
- 2003-01-15 US US10/342,968 patent/US20030180375A1/en not_active Abandoned
-
2007
- 2007-01-04 US US11/650,211 patent/US8143317B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5228434A (en) * | 1991-07-16 | 1993-07-20 | Praxair Technology, Inc. | Mixture for anesthesia |
US6274633B1 (en) * | 1999-07-29 | 2001-08-14 | Imperial College Of Science, Technology, And Medicine | NMDA antagonist |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006017524A3 (en) * | 2004-08-02 | 2006-08-31 | John W Olney | Preventing pathological increases in the rate of nerve cell suicide in immature nervous systems |
WO2007075100A1 (en) * | 2005-12-27 | 2007-07-05 | Zakrytoe Aktsionernoe Obshchestvo 'atom-Med Center' | Method for treating drug dependence |
US10369103B2 (en) | 2012-08-10 | 2019-08-06 | The Board Of Regents Of The University Of Texas System | Neuroprotective liposome compositions and methods for treatment of stroke |
US10973764B2 (en) | 2012-08-10 | 2021-04-13 | The Board Of Regents Of The University Of Texas System | Neuroprotective liposome compositions and methods for treatment of stroke |
US11872312B2 (en) | 2012-08-10 | 2024-01-16 | The Board Of Regents Of The University Of Texas Systems | Neuroprotective liposome compositions and methods for treatment of stroke |
US11491184B2 (en) | 2013-03-15 | 2022-11-08 | The Board Of Regents Of The University Of Texas System | Liquids rich in noble gas and methods of their preparation and use |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8143317B2 (en) | Use of xenon for treating neurointoxications | |
BRANDRUP | Tetrabenacine treatment in persisting dyskinesia caused by psychopharmaca | |
JP2022136154A (en) | Composition for treating schizophrenia | |
AU2004283448B2 (en) | Use of xenon for the prevention of programmed cell death | |
EP1552840A1 (en) | Use of a xenon/carbon monoxide mixture for the protection of cells | |
JPH08500343A (en) | Treatment method using cesium ion | |
ES2248153T3 (en) | USE OF NITRIC OXIDE FOR THE TREATMENT OF AIRCRAFT CONSTRUCTION. | |
MXPA01009121A (en) | Use of xenon for treating neurointoxications | |
US20230211112A1 (en) | Method for emergency relief of acute ischemic attacks | |
MX2023008155A (en) | Treatment regimens with fixed doses of tamibarotene. | |
MXPA06004505A (en) | Use of xenon for the prevention of programmed cell death | |
ATE394141T1 (en) | USE OF PHENAZONE TO TREAT MIGRAINES |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |