EP1651243A2

EP1651243A2 - Inhalable gaseous medicine based on xenon and nitrous oxide

Info

Publication number: EP1651243A2
Application number: EP04767913A
Authority: EP
Inventors: Jacques Abraini; Marc Lemaire
Original assignee: Air Liquide Sante International SA
Current assignee: Air Liquide Sante International SA
Priority date: 2003-07-30
Filing date: 2004-07-23
Publication date: 2006-05-03
Also published as: AU2004260859B2; US20090252816A1; CN1829522A; WO2005011711A2; WO2005011711A3; CN1829522B; FR2858233A1; JP2007500174A; AU2004260859A1; US20070053992A1; FR2858233B1; CA2533499A1

Abstract

The invention concerns the use of a gaseous mixture containing gas xenon and gas nitrous oxide, and advantageously oxygen, for making all or part of an inhalable medicine for preventing or treating neurointoxication in a human. The xenon/nitrous oxide mixture of the invention acts on one or more cerebral receptors to reduce the release and/or the effects of dopamine, glutamate, serotonin, taurin, GABA, noradrenaline and/or any other neurotransmitter. The proportion by volume of xenon of the mixture ranges between 5 and 45 %, and the proportion by volume of nitrous oxide ranges between 10 and 50 %, the balance is preferably oxygen.

Description

Inhalable gaseous drug based on xenon and nitrous oxide

The invention relates to the use of a gas mixture containing xenon and nitrous oxide (N ₂ 0) for manufacturing all or part of an inhalable medicament intended to treat or prevent a pathology having a neurotoxic effect, c is neuro-intoxication, in particular the neurotoxic effects of drugs or other addictive substances. In pathologies linked to the neurotoxic effects of addictive drugs, such as amphetamines, it is recognized that dopaminergic neurotransmission of nigrostriatal and mesolimbic origin participates in the psycho-stimulating and neurotoxic effects of these drugs. However, recent work by Del Arco et al., Neuropharmacology, 38: 943,

1999, showed that the facilitating effects of amphetamines are not limited to dopaminergic neurotransmission. Thus, at the striatum-nucleus accumbens complex, amphetamines induce not only an increase in the release of dopamine but also an increase in the release of serotonin, taurine, γ-amino-butyric acid (GABA), and glutamate. In a particularly interesting way, it has been shown that the specific inhibition of glutamate transporters makes it possible to reduce both hyperactivity (David, Thévenoux and

Abraini, Neuropharmacology, 2001) and increased glutamate, but not dopamine

(Del Arco et al., Neuropharmacology 38: 943, 1999), following the injection of amphetamines, thus suggesting a decisive role for glutamate in the psychostimulatory effects of amphetamines. Furthermore, recent work, carried out in vitro, has shown that xenon and nitrous oxide (N ₂ 0) can behave as antagonists of low affinity for glutamatergic receptors for N-Methyl-D-Aspartate (N DA ; Franks et al., Nature 396:

324, 1998; Jevtovic-Todorovic et al., Nature Med. 4: 460, 1998). In addition, as part of the study of the endogenous hyperalgesic opioid system in the negative placebo response, FJ Lichtigfeld and MA Gillman, Intem. J. Neuroscience, 1989, vol. 49, p. 71-74 conclude that nitrous oxide has an effect on alcohol withdrawal a little better than the placebo effect, although, for more than 50% of individuals, an identical positive effect was also observed with the placebo. However, the same authors add, in Nitous Oxide and the Aws, p. 785, that the beneficial effect of nitrous oxide depends closely on its concentration because anesthetic or pre-anesthetic concentrations are ineffective, even counterproductive in certain cases; an analgesic concentration being recommended. Yet another publication by these authors, published in Intem. J. Neuroscience, 1994, Vol. 76, p. 17 -33, underlines the rapid and lasting effects of nitrous oxide psychotropic analgesic in the mechanism of alcohol withdrawal. In Postgrad. ed. J, Clinical Toxicology, 1990, 66, p. 543-546, the same authors explain that the nitrous oxide concentrations can vary from less than 15% to more than 70% depending on the individual, depending on their degree of alcohol dependence. Furthermore, document EP-A-1158992 teaches the use of xenon or a mixture of xenon with oxygen, nitrogen or air to treat neuro-intoxication. However, the use of xenon or of the mixtures described by this document is not entirely satisfactory in practice, in particular because of the appearance of toxicity for certain xenon contents and taking into account the high cost of this compound. In addition, US-A-6,274,633 teaches the use of xenon as a compound antagonist of the NMDA receptors presumed implicated in the neurotoxicity and the death of the neuronal cells caused by certain diseases or ischemic hypoxias or consecutive to a cardiac arrest in particular. In addition, EP-A-861672 proposes inhalable gas mixtures based on oxygen and several possible gases including xenon. Finally, FR-A-2596989 proposes gas mixtures based on nitrous oxide and oxygen, which may optionally contain xenon or other gases, as radio-sensitization products, in particular usable in cancer radiotherapy. The present invention is part of this context and aims to improve existing inhalable drugs intended to prevent or effectively treat a state of addiction in humans, that is to say any disorder, disorder or pathology related to the effects neurotoxic, particularly the neurotoxic effects of addictive drugs. The solution of the invention then relates to the use of a gaseous mixture containing gaseous xenon (Xe) and gaseous nitrous oxide (N2O) to manufacture all or part of an inhalable medicament intended for preventing or treating neuro-intoxication in humans, the volume proportion of xenon being between 5 and 45% and the volume proportion of nitrous oxide being between 10 and 50%. Depending on the case, the use of the invention may include one or more of the following technical characteristics: - neuro-intoxication results from a cerebral excess of one or more neurotransmitters. - The mixture containing xenon and nitrous oxide acts on at least one brain receptor so as to reduce the effects and / or the release of dopamine, glutamate, serotonin, taurine, GABA, noradrenaline and / or any other neurotransmitter. - The volume proportion of xenon is between 20 and 40% and the volume proportion of nitrous oxide is between 10 and 40%. the volume proportion of xenon is between 20 and 32% and the volume proportion of nitrous oxide is between 20 and 40%, preferably the volume proportions of xenon and nitrous oxide are each of the order of 30%. the volume proportion of xenon is between 10 and 20% and the volume proportion of nitrous oxide is between 40 and 50%, preferably the volume proportion of xenon is of the order of 16% and the volume proportion of nitrous oxide is around 50%. - The drug also contains oxygen, an oxygen / nitrogen mixture or air, preferably the gas mixture consists of xenon, nitrous oxide and oxygen for the rest. - neuro-intoxication is of the type causing a state of addiction, that is to say a disorder, disorder or pathology linked to the neurotoxic effects of a drug, molecule or substance generating addiction, dependence and / or addiction in humans or animals. The substance, drug or molecule generating the addiction is chosen from the group formed by amphetamines and their derivatives, cocaine, tobacco, alcohol and cannabis, or any other similar or analogous drug. - the inhalable drug is conditioned at a pressure of 2 bars to 350 bars, preferably between 2 bars and 200 bars. - the drug is ready-to-use, that is, it can be administered to the patient directly without undergoing pre-dilution. The invention also relates to a gaseous inhalable medicament containing from 5 to 35% by volume of xenon and from 10 to 50% by volume of nitrous oxide, and optionally oxygen. Depending on the case, the gas mixture of the invention may comprise one or more of the following technical characteristics: - it consists of 5 to 32% by xenon volume, 10 and 50% of nitrous oxide, and oxygen for the rest. - It consists of 20 to 32% by volume of xenon, 20 and 40% of nitrous oxide, and oxygen for the rest, preferably the volume proportions of xenon and nitrous oxide are each of the around 30%. - It consists of 10 to 20% by volume of xenon, 45 and 50% of nitrous oxide and oxygen for the rest, preferably the volume proportion of xenon is of the order of 16% and the volume proportion nitrous oxide is around 50%. In other words, the idea underlying the present invention is therefore that the antagonistic properties of the NMDA receptors of xenon and of nitrous oxide can be used, in a combined or synergistic manner, for their neuroprotective character in the prevention and / or the treatment of disorders or disorders linked to neurotoxic effects, in particular the neurotoxic effects of addictive drugs, such as amphetamines and their derivatives, cocaine, tobacco, alcohol, cannabis or any other substance causing dependence, including all or part of an inhalable gaseous drug In general, the medicament according to the invention can be administered to the patient via his upper airways, that is to say by inhalation via his nose and / or his mouth, by means of a suitable administration device comprising a patient breathing interface, such as a breathing mask or tracheal tube, one or more supply lines to deliver the gaseous medication from a source containing the medication to the interface, and a medical ventilator to deliver and / or extract the patient's gas. The invention also relates to a method for preventing or treating neurointoxication in a human patient, in which a gaseous mixture containing gaseous xenon and nitrous oxide gas is administered by inhalation to said patient, the volume proportion of xenon in said gas mixture being between 5 and 45% and the volume proportion of nitrous oxide being between 10 and 50%.

Examples: Demonstration of the neuroprotective potential of xenon and nitrous oxide

In order to evaluate the neuroprotective potential of xenon and nitrous oxide gas, whose antagonistic properties of glutamatergic receptors of the NMDA type have been recently highlighted, on sensitization to amphetamines, behavioral, neurochemical and histological studies have been carried out as described below. Male Sprague-Dawley rats weighing approximately 250 g were used during the experiments. During the tests, the d-amphetamine awareness protocol and the nitrous oxide and xenon treatment trials were as follows. 15 groups of animals (of 7 or 8 animals each) were used, including 10 groups during the actual sensitization studies and 5 other groups during the histological studies of the neurons of the posterior and retrosplenial cingulate cortex. The animals were injected intraperitoneally (ip) for 3 consecutive days from D1 to D3, with d-amphetamine (Amph; 1 mg / ml / kg) or, as the case may be, saline solution (1 ml / kg) for control animals. After each injection, the rats were immediately placed for 3 hours in a closed enclosure, with a volume of 100 liters, swept in dynamic regime at a constant flow rate of 5 l.min- ¹ , either by air (Group 1 : saline; Group 2: Amph), either with nitrous oxide at 50% by volume (Group 3: saline; Group 4: Amph) or 75% (Group

5: saline; Group 6: Amph), i.e. with xenon at 50% by volume (Group 7: saline; Group

8: Amph) or 75% (Group 9: saline; Group 10: Amph); the rest of the mixtures

(100% complement) being oxygen. In order to identify the possible neurotoxic potential of repeated exposure (3h per day for 3 hours) to nitrous oxide or xenon at the level of the posterior cingulate cortex and retrosplenial, 5 additional groups of animals were pretreated, according to a protocol identical to that defined above, by administration of a saline solution and then exposed either to air (Group 11) or to protoxide nitrogen at 50 or 75% (Groups 12 and 13), or xenon at 50 or 75% (Groups 14 and 15). The locomotor activity of animals in groups 1 to 10 was evaluated on D6, after an ip injection of saline solution (1 ml / kg), and on D7 after a ip injection of d-amphetamine (1 mg / ml / kg). The locomotor activity of animals in response to these injections was recorded using actimetry cages with photoelectric cells (Imétronic, Pessac, France). In addition, neurochemical studies, in addition to the histological and behavioral studies above, were carried out on slices of the brains of these rats in order to identify the mechanisms of the action of nitrous oxide and xenon, and in order to assess the neurotoxic potential of nitrous oxide and xenon. To do this, after treatment, the animals were sacrificed on D8 by decapitation under general anesthesia with halothane, then the cranial box immediately placed in a solution of paraformaldehyde for one week. The brain was removed, embedded in paraffin and sectioned into 4 μm frontal sections mounted on gelatinized slides and stained with a hemalun-eosin-saffron solution. The posterior and retrosplenial cingulate cortices were analyzed under an optical microscope (x 400). In addition, the preparation of accumbens core slices was carried out as follows. The animals were decapitated under light halothane anesthesia, then the brain quickly removed. Front sections of 300 μm, corresponding to an anteriority of + 0.70 / 1.20 mm (compared to Bregma, Paxinos and Watson, 1998), were taken using a chopper (Mickie Laboratory Engineering Company, Gomshall, Surrey , UK). The brain slices were placed for recovery in buffered saline at a temperature of 3-4 ° C for at least 1 hour before use for neurochemical study. The measurement of dopamine release was carried out by the normal differential pulse voltammetry technique using a single fiber carbon electrode with a diameter of 10 μm and length 250 μm (CFN10-250; World Precision Instruments, Aston,

Stevenage, Hertfordshire, UK). The electrochemical treatment making it possible to make this type of electrode sensitive to dopamine, consisted in the application in a buffered phosphate saline solution of a direct current of -1.5 V for 20 s, then of a current +2.6 V triangular for also 20 s on the working electrode (Brazell et al., 1987). Under these conditions, the dopaminergic signal appears at a potential of + 100 mV. The rat brain slices were then placed in an organ tank and perfused with an artificial cerebrospinal fluid of composition: NaCI 118mM, MgCI∑ 1.18 mM, KCI 4.9 mM, NaH ₂ P0 ₄ 1.25 mM, CaCI ₂ 1.25 mM, NaHC0 ₃ 3.6 mM, d-glucose 10 mM, HEPES 30 mM, pH 7.4, whose temperature was regulated to 34 ± 1 ° C by means of a temperature controller (Delta 4 Culture Dish Controller, Bioptechs, Butler, PA, USA) . The electrode was placed under microscopic control (EFN 600 microscope, Nikon, Paris, France), 100 μm from the anterior commissure, using an optical micrometer incorporated into the microscope, then completely lowered into the accumbens nucleus, according to an angle of 45 °, and connected to the Biopulse polarograph set in normal differential pulse voltammetry mode with the following parameters: scanning potential -150 + 350 mV; scanning time 0.4s, scanning amplitude 4 mV, for a scanning speed of 10 mV.s- ¹ ; measurement pulse 40 ms; measurement pre-pulse 70 ms; measuring range 30 mV. Dopaminergic hyperstimulation was induced by adding d-amphetamine to the infusion fluid, medical air, nitrous oxide or xenon was dissolved, until saturation, before use in the infusion fluid, including pH was readjusted to 7.4. D-amphetamine (d-amphetamine sulfate, ref. A5880) was acquired after authorization from the narcotic and psychotropic unit of the French Agency for Sanitary Safety of Health Products from Sigma-AIdrich (Illkirch, France). Medical air, nitrous oxide and xenon were supplied by Air Liquide Santé International (Paris, France). The mixtures based on nitrous oxide, oxygen and / or xenon were produced, using calibrated flow-liters also supplied by Air Liquide Santé International. The results obtained, recorded in Figures 1 and 2 attached, are expressed as the mean ± standard error. The comparison of the groups was carried out by means of non-parametric tests: the analysis of variance of Kruskall-Wallis, supplemented in the event of a significant result of the Mann-Whitney U test. More precisely, at the behavioral level, the histograms on the left of FIGS. 1 and 2 illustrate the sensitization process induced by the repeated administration of d-amphetamine since: - Figure 1 shows the effects of nitrous oxide at 50 vol% and 75 vol% (oxygen rest) on awareness of d-amphetamine; and - Figure 2 illustrates the effects of xenon at 50% and 75% on sensitization to d-amphetamine. It can be seen in these Figures that the repeated injection of d-amphetamine produces an increase in locomotor activity induced by the acute injection of d-amphetamine, so that the locomotor activity of animals pretreated with d-amphetamine ( amph in the Figure) appears significantly higher than that of the control animals pretreated with a saline solution (saline in the Figure), during the d-amphetamine test carried out on D7 (P <0.05). On the other hand, a repeated injection of D1 to D3 of d-amphetamine produced no significant difference in locomotor activity between the animals pretreated with d-amphetamine and the control animals in response to the saline test carried out on D6. With regard to FIG. 1, it can be seen that, under the above experimental conditions, exposure to nitrous oxide, immediately after pretreatment with d-amphetamine, induces a dose-dependent blockade of the sensitization process. Thus, the locomotor activity of animals pretreated with d-amphetamine and nitrous oxide at 50 vol% induced by the d-amphetamine test carried out on D7 does not appear to be significantly different from the motor activity of pretreated rats. with a saline solution and nitrous oxide at 50 vol%, or that of animals pretreated with d-amphetamine and in air. This result shows a partial blockage of the sensitization process, under the experimental conditions above. Exposure to nitrous oxide at 75 vol%, immediately after pretreatment with d-amphetamine, produces a significant blockage of the sensitization process, so that the locomotor activity of animals pretreated with d-amphetamine and protoxide of nitrogen at 75 vol% induced by the d-amphetamine test carried out on D7 appears significantly lower than that of animals pretreated with d-amphetamine and in air (P <0.05), but not significantly different from that of animals pretreated with 75 vol% saline and nitrous oxide. Furthermore, no 'gas' effect was found in rats pretreated with saline during the acute d-amphetamine test carried out on D7, which shows that N20 blocks awareness raising at the origin of states of addiction and dependence but has no effect on acute drug administration. Similarly, no significant difference in motor activity was found in response to the saline test on D6, which shows that the gases have no long-term sedative effect. With regard to FIG. 2, it can be seen that, under the above experimental conditions, whatever the concentration of xenon used, ie 50 vol% or 75 vol%, the locomotor activity of animals pretreated with d-amphetamine and with xenon induced by the challenge to d-amphetamine performed on D7 produces a blocking of sensitization to d-amphetamine, so that the locomotor activity of animals pretreated with d-amphetamine and xenon appears significantly lower than that of animals pretreated with d-amphetamine and air (P <0.05), but not different from that of animals pretreated with saline and xenon. As with nitrous oxide (Fig. 1), no significant difference in locomotor activity was found in response to the saline test on D6, which again demonstrates that the gases have no sedative effect at long term. In contrast, in animals pretreated with saline, there was a significant increase in the response to d-amphetamine in animals given xenon at 75 vol%, compared to animals pretreated with air or xenon at 50 vol%, which could account for sensitization of the NMDA receptors and a possible toxic effect of xenon at high dose, that is to say of the order of 75% by volume. In addition, a histological study of the posterior and retroplenial cingulate cortex shows in rats exposed to xenon at 75 vol% a generalized cytoplasmic clarification associated with a picnotic aspect of the cell nuclei, as well as the appearance in some animals of cytoplasmic vacuoles, which suggest , in accordance with motor activity, a neurotoxic effect of repeated administration, 3 consecutive days, of xenon at 75 vol%. No similar effect was found in rats exposed to medical air, 75 vol% nitrous oxide, or 50 vol% xenon. Furthermore, Figure 3 illustrates the effects of nitrous oxide on the increase in dopamine release in the nucleus accumbens induced by d-amphetamine. Identical results were obtained with 50% xenon. The addition of d-amphetamine at 10 ^{~ 5} M generates a significant increase in the signal compared to the measured base signal (P <0.05). This increase in dopamine release in the accumbens nucleus is significantly reduced in the presence of 75% nitrous oxide or 50% xenon (in vol.) In the perfusion fluid (P <0.05). Without the addition of d-amphetamine, the signal remains stable for the duration of the experiment. Ultimately, the results obtained clearly show that nitrous oxide and xenon have inhibitory effects on sensitization to d-amphetamine and the release of dopamine associated with it. Thus, the simultaneous exposure of animals to nitrous oxide or to xenon during the awareness phase to d-amphetamine completely blocks, in the case of nitrous oxide at 75 vol% or xenon at 50 vol% and 75 vol%, locomotor hyperactivity due to sensitization in response to acute administration of d-amphetamine. Considering that nitrous oxide and xenon show no effect on glutamatergic receptors of the AMPA type (Yakamura and Harris, 2000), their inhibitory effects can be attributed to their antagonistic properties of glutamatergic receptors of the type NMDA (Jevtovic-Todorovic et al., 1998; Franks et ai, 1998; Yakamura et ai, 2000) but also their antagonistic properties of nicotinic type cholinergic receptors and their agonist properties of type A GABAergic receptors. administration of NMDA type glutamatergic receptor antagonists with amphetamines makes it possible to block the sensitization process and the dopamine release associated with it. Furthermore, the results obtained also show that 75 vol% of nitrous oxide and only 50 vol% of xenon are necessary to block the sensitization process. However, in view of the behavioral and histological effects observed with high-content xenon, the use of 75% xenon is not recommended. Indeed, the animals pretreated (from D1 to D3) with a saline solution and xenon at 75% show a locomotor activity greater than that of the control animals pretreated with saline + air, during the d-amphetamine test (performed on D7), which could account for sensitization of the NMDA receptors. In addition, 75% xenon generates cytoplasmic clarification aggravated, in a few cases, by vacuolation of the neurons of the posterior and retrosplenial cingulate cortices, which undoubtedly signals a neurotoxic process. In other words, nitrous oxide at 75 vol. % or xenon at 50 vol.% and 75 vol.% block the process of behavioral sensitization to d-amphetamine but xenon at 75 vol% also induces an increase in the acute response to d-amphetamine which could reflect a modification receptor sensitivity and a potentially deleterious process, which supports histological studies. In addition, nitrous oxide and xenon at 50 vol% or 75 vol% block the increase in dopamine release induced by d-amphetamine. All these results show the undeniable inhibitory effects of nitrous oxide and xenon on awareness of d-amphetamine and the neurochemical processes associated with it. From there, to benefit from the advantages provided by xenon but without generating the deleterious or neurotoxic effects mentioned above, in particular in the case of more severe neuropathies presenting an excitotoxic glutamatergic component, and without being penalized by the high cost of this gas, it is then recommended to use not xenon alone but rather a gaseous mixture formed of xenon and nitrous oxide, the xenon content having to be kept very far from the toxicity threshold of this compound, that is to say typically less than or equal to about 60% in humans (evening about 75% in rats). Thus, gas mixtures containing 5 and 35% by volume of xenon gas and 10 and 50% by volume of nitrous oxide gas (and oxygen for the rest) are entirely suitable for use as inhalable gas drug used to prevent or treat neuro-intoxication in humans or animals. Indeed, by using suitable mixtures based on xenon and nitrous oxide, one can benefit from the effects of these two compounds without encountering the above-mentioned problems. The gas mixture of the invention can be used to treat all neurointoxications. Neuro-intoxication means a disorder, disorder or pathology of the central nervous system, the etiopathogeny of which involves, at least in part, an excito-toxic process, in particular a dysfunction of the excitatory neurotransmission to glutamate; see in particular the document Parsons et al., Drug News Perspect, 1998, vol.11, pages 523-569. Consequently, it is within the scope of the present invention not only the treatment of the neurotoxic effects of drugs or other substances capable of generating an addiction such as amphetamines and amphetamine derivatives, opiate substances and their derivatives, cocaine and its derivatives, tobacco, cannabis and / or alcohol, but also acute stroke such as head trauma and stroke, including cerebral ischemia; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease (chorea), amyotrophic lateral sclerosis, acute disseminated encephalomyelitis, tardive dyskinesia, and olivopontocerebellar degeneration; and various psychiatric or neurological pathologies such as anxiety disorders, psychotic disorders, in particular schizophrenia and epilepsy in its various forms.

Claims

claims

1 - Use of a gas mixture containing gaseous xenon and nitrous oxide gas to manufacture all or part of an inhalable medicament intended to prevent or to treat a neuro-intoxication in man, the proportion by volume of xenon being between 5 and 45% and the volume proportion of nitrous oxide being between 10 and 50%. 2 - Use according to claim 1, characterized in that the neuro-intoxication results from a cerebral excess of one or more neurotransmitters. 3 - Use according to one of claims 1 or 2, characterized in that the mixture containing xenon and nitrous oxide acts on at least one brain receptor so as to decrease the release and or the effects of dopamine, glutamate, serotonin, taurine, GABA, noradrenaline and / or any other neurotransmitter. 4 - Use according to one of claims 1 to 3, characterized in that the gas mixture contains oxygen for the rest. 5 - Use according to one of claims 1 to 4, characterized in that the volume proportion of xenon is between 20 and 40% and the volume proportion of nitrous oxide is between 10 and 40%. 6 - Use according to one of claims 1 to 5, characterized in that the volume proportion of xenon is between 20 and 32% and the volume proportion of nitrous oxide is between 20 and 40%, preferably the proportions xenon and nitrous oxide volumes are each of the order of 30%. 7 - Use according to one of claims 1 to 4, characterized in that the volume proportion of xenon is between 10 and 20% and the volume proportion of nitrous oxide is between 40 and 50%, preferably the proportion the volume of xenon is of the order of 16% and the volume proportion of nitrous oxide is of the order of 50%. 8 - Use according to one of claims 1 to 7, characterized in that the medicament additionally contains oxygen, an oxygen / nitrogen mixture or air, preferably the gaseous mixture consists of xenon, nitrous oxide and oxygen for the rest. 9 - Use according to one of claims 1 to 8, characterized in that the medicament is ready-to-use. 10 - Use according to one of claims 1 to 9, characterized in that the neuro-intoxication is of the type generating a state of addiction. 11 - Gaseous mixture containing 5 to 35% by volume of xenon and 10 and 50% by volume of nitrous oxide as an inhalable medicament. 12 - Gaseous mixture according to claim 11, characterized in that it additionally contains oxygen. 13 - Mixture according to one of claims 11 or 12, characterized in that it consists of 20 to 32% by volume xenon, 20 and 40% of nitrous oxide and oxygen for the rest. 14 - Mixture according to one of claims 10 to 13, characterized in that the volume proportions of xenon and nitrous oxide are each of the order of 30%. 15 - Mixture according to one of claims 11 to 13, characterized in that it consists of 10 to 20% by xenon volume, 45 and 50% of nitrous oxide and oxygen for the rest, preferably the volume proportion of xenon is of the order of 16% and the volume proportion of nitrous oxide is of the order of 50%.