US 2009025281 6A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0252816A1 Abraini et al. (43) Pub. Date: Oct. 8, 2009 (54) NHAILABLE GASEOUSMEDICAMENT (30) Foreign Application Priority Data BASED ON XENON AND NITROUS OXDE Jul. 30, 2003 (FR) ....................................... O350383 (75) Inventors: Jacques Abraini, Caen (FR); Marc Lemaire, Paris (FR) Publication Classification Correspondence Address: (51) Int. Cl. AIR LIQUIDE A633/00 (2006.01) Intellectual Property (52) U.S. Cl. ........................................................ 424/718 2700 POST OAKBOULEVARD, SUITE 1800 HOUSTON, TX 77.056 (US) (57) ABSTRACT (73) Assignee: AIR LIQUIDE SANTE The invention concerns the use of a gaseous mixture contain (INRTERNATIONAL), Paris (FR) ing gas Xenon and gas nitrous oxide, and advantageously oxygen, for making all or part of an inhalable medicine for (21) Appl. No.: 12/417,087 preventing or treating neurointoxication in a human. The Xenon/nitrous oxide mixture of the invention acts on one or (22) Filed: Apr. 2, 2009 more cerebral receptors to reduce the release and/or the effects of dopamine, glutamate, serotonin, taurin, GABA, Related U.S. Application Data noradrenaline and/or any other neurotransmitter. The propor (62) Division of application No. 10/563,278, filed on Oct. tion by volume of xenon of the mixture ranges between 5 and 6, 2006, filed as application No. PCT/FR2004/050352 45%, and the proportion by Volume of nitrous oxide ranges on Jul. 23, 2004. between 10 and 50%, the balance is preferably oxygen. Patent Application Publication Oct. 8, 2009 Sheet 1 of 3 US 2009/025281.6 A1 4OO >- - -- r" " - - ----...--. is 200 - r --- C) s O os T O C) O - - s SH r 7 |7 || 7 |7 AR. N2007. NC 757. Petreatment saline amph satine aniel Safarig" Challenge Salamhsalanph salamphsalamph Salai Eph Satangh * P40,05 FG. Patent Application Publication Oct. 8, 2009 Sheet 2 of 3 US 2009/025281.6 A1 1400 +----------- >s 1200 ------------ - - - - - rs1-------------------------. a. 600. 8 go | | | | | | | 2CO - || || 2 O els Itlast Isle88 als 8 re? R. Xe 50 5. Pretreatment satine anph saline amph saline art ph Challenge Salamphsala?iph Salamisalarnph Salamhsalamph - P.C. C. OS FG, 2 water Patent Application Publication Oct. 8, 2009 Sheet 3 of 3 US 2009/025281.6 A1 F-89:28 lessefixeig: SAEEE S.A., Avi Pi AMPH 75% NO US 2009/025281.6 A1 Oct. 8, 2009 NHAILABLE GASEOUSMEDICAMENT underlines the rapid and long-lasting psychotropic analgesic BASED ON XENON AND NITROUS OXDE effects of nitrous oxide in the mechanism of weaning from alcohol. CROSS REFERENCE TO RELATED (0011. In Postgrad. Med. J. Clinical Toxicology, 1990, 66, APPLICATION pp. 543-546, the same authors explain that the nitrous oxide concentrations may vary from less than 15% to more than 0001. This present application is a divisional of U.S. 70% depending on the individual, as a function of his or her patent application Ser. No. 10/563.278 which has a U.S. filing degree of alcohol dependency. date of Oct. 6, 2006 and which is a S371 of International PCT 0012 Moreover, document EP-A-1 158992 teaches the Application PCT/FR2004/050352, filed Jul. 23, 2004. use of Xenon or of a mixture of Xenon with oxygen, nitrogen or air to treat neurointoxications. However, the use of Xenon FIELD OF INVENTION or of the mixtures described by said document is not entirely 0002 The invention relates to the use of a gaseous mixture satisfactory in practice, especially due to the appearance of containing Xenon and nitrous oxide (N2O) to manufacture all toxicity for certain Xenon contents and given the high cost of or part of an inhalable medicament for treating or preventing this compound. a pathology with a neurotoxic effect, i.e. neurointoxication, 0013 Moreover, U.S. Pat. No. 6,274,633 teaches the use especially the neurotoxic effects of drugs or other addictive of Xenon as an NMDA receptor antagonist compound Substances. assumed to be involved in neurotoxicity and neuronal cell death caused by certain diseases or ischemic hypoxia or fol BACKGROUND lowing a heart attack, in particular. 0014. In addition, EP-A-861 672 proposes inhalable gas 0003. In pathologies associated with the neurotoxic eous mixtures based on oxygen and on several possible gases, effects of addictive drugs, such as amphetamines, it is including Xenon. accepted that dopaminergic neurotransmission of nigrostri 0015 Finally, FR-A-2596989 proposes gaseous mixtures atal and mesolimbic origin participates in the psychoStimu based on nitrous oxide and oxygen, which may possibly lant and neurotoxic effects of these drugs. contain Xenon or other gases, as radiosensitizing products, 0004. However, recent studies by Del Arco et al., Neurop which may especially be used in cancer radiotherapy. harmacology, 38: 943, 1999, have shown that the facilitating 0016. The present invention falls within this context and is effects of amphetamines are not limited to dopaminergic neu directed toward improving the existing inhalable medica rotransmission. ments intended for effectively preventing or treating a state of 0005 Thus, in the striatum-nucleus accumbens septicom addiction in humans, i.e. any condition, disorder or pathology plex, amphetamines induce not only an increase in dopamine associated with neurotoxic effects, in particular the neuro release but also an increase in serotonin, taurine, Y-aminobu toxic effects of addictive drugs. tyric acid (GABA) and glutamate release. 0006. It has been shown, particularly advantageously, that SUMMARY OF THE INVENTION the specific inhibition of glutamate transporters makes it pos sible to reduce both hyperactivity (David, Thévenoux and 0017. The solution of the invention thus relates to the use Abraini, Neuropharmacology, 2001) and the increase in of a gaseous mixture containing Xenon (Xe) gas and nitrous glutamate, but not in dopamine (Del Arco et al., Neurophar oxide (NO) gas to manufacture all or part of an inhalable macology 38: 943, 1999), following injection of amphet medicament for preventing or treating a neurointoxication in amines, thus suggesting a decisive role of glutamate in the man, the volume proportion of xenon being between 5% and psychostimulant effects of amphetamines. 45% and the volume proportion of nitrous oxide being 0007 Moreover, recent studies, performed in vitro, have between 10% and 50%. shown that xenon and nitrous oxide (N2O) can behave like antagonists with low affinity for the N-methyl-D-aspartate BRIEF DESCRIPTION OF THE FIGURES glutamatergic receptors (NMDA: Franks et al., Nature 396: 0018 FIG. 1 illustrates the effects of nitrous oxide at 50 324, 1998; Jevtovic-Todorovic et al; Nature Med. 4: 460, vol % and 75 vol % (with the remainder of oxygen) on 1998). sensitization to d-amphetamine. 0008. In addition, in the context of the study of the endog 0019 FIG. 2 illustrates the effects of xenon at 50% and enous hyperalgesic opioid system in the negative placebo 75% on sensitization to d-amphetamine. response, F. J. Lichtigfeld and M. A. Gillman, Intern. J. Neu 0020 FIG. 3 illustrates the effects of nitrous oxide on the roscience, 1989, Vol. 49, pp.71-74 conclude that the effect of increase in dopamine release in the nucleus accumbens septi nitrous oxide on weaning from alcohol is slightly better than induced with d-amphetamine. the placebo effect, although, for more than 50% of the indi viduals, an identical positive effect was also found with the placebo. DETAILED DESCRIPTION OF THE INVENTION 0009. However, the same authors add, in Nitrous Oxide 0021. The present invention relates to the use of a gaseous and the Aws, p. 785, that the beneficial effect of nitrous oxide mixture containing Xenon gas and nitrous oxide gas in order depends closely on its concentration, since anesthetic or pre to manufacture all or part of an inhalable medicament for anesthetic concentrations are ineffective, or are even counter preventing or treating neurointoxication in man. productive in certain cases, an analgesic concentration being 0022 Depending on the case, the use of the invention may recommended. include one or more of the following technical characteristics: 0010 Yet another publication from these authors, pub 0023 the neurointoxication results from a cerebral lished in Intern. J. Neuroscience, 1994, Vol. 76, pp. 17-33, excess of one or more neurotransmitters, US 2009/025281.6 A1 Oct. 8, 2009 0024 the mixture containing xenon and nitrous oxide and derivatives thereof, cocaine, tobacco, alcohol, cannabis acts on at least one cerebral receptor so as to reduce the or any other dependency-generating Substance, especially all effects and/or the release of dopamine, glutamate, sero or part of an inhalable gaseous medicament. tonin, taurine, GABA, noradrenalin and/or any other 0038. In general, the medicament according to the inven neurotransmitter, tion may be administered to the patient via his upper respira 0025 the volume proportion of xenon is between 20% tory pathways, i.e. by inhalation via the nose and/or the and 40% and the Volume proportion of nitrous oxide is mouth, using a suitable administration device comprising a between 10% and 40%, patient respiratory interface, such as a respiratory mask or 0026 the volume proportion of xenon is between 20% tracheal probe, one or more feed pipes serving to convey the and 32% and the Volume proportion of nitrous oxide is gaseous medicament from a source containing said medica between 20% and 40%, and preferably the volume pro ment to the interface, and a medical ventilator serving to portions of Xenon and of