WO2011154630A1 - Krypton-based inhalable gaseous medicinal product for combatting deficiencies or failure of peripheral organs - Google Patents

Krypton-based inhalable gaseous medicinal product for combatting deficiencies or failure of peripheral organs Download PDF

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WO2011154630A1
WO2011154630A1 PCT/FR2011/051112 FR2011051112W WO2011154630A1 WO 2011154630 A1 WO2011154630 A1 WO 2011154630A1 FR 2011051112 W FR2011051112 W FR 2011051112W WO 2011154630 A1 WO2011154630 A1 WO 2011154630A1
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krypton
composition according
deficiency
failure
organ
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PCT/FR2011/051112
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French (fr)
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Marc Lemaire
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L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude
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Publication of WO2011154630A1 publication Critical patent/WO2011154630A1/en

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of krypton gas to manufacture all or part of an inhalable medicament for treating or preventing organ deficiency or failure, in particular of an organ selected from the brain, kidneys, heart , the liver and the lungs, whether this deficiency is isolated or multiple.
  • the deficiency or failure of an organ is characterized by an organic and / or functional abnormality of the organ considered, that is to say an incapacity or an impossibility of this organ to present a normal functionality.
  • This deficiency or failure can be transient, that is to say, last from less than an hour to several days or weeks, or definitive.
  • the cause of a deficiency or organ failure can be related in particular to an abnormality / deficit of vascularization, for example the ischemia-reperfusion, or of oxygenation, to a localized or generalized infection, an acute or chronic inflammation localized or generalized, primary or secondary autoimmunity phenomena, trauma, organo-degeneration ...
  • an abnormality / deficit of vascularization for example the ischemia-reperfusion, or of oxygenation
  • the deficiency or failure can affect several organs concomitantly and one speaks then of multi-organ deficiency.
  • EP-A-1158992 proposes to use inhaled xenon to fight against cerebral neuro-intoxications, particularly ischemic, which are characterized by cerebral dysfunction of one or more neurotransmission systems.
  • EP-A-1541 156 proposes for its part to use inhaled argon to fight against said brain neuro-intoxications.
  • the document proposes argon gas to manufacture all or part of an inhalable drug intended to treat or prevent a disability.
  • EP-A-1651243 proposes meanwhile to use mixtures Xe / N 2 0 inhaled for this purpose, while the DE-A-19991033704 provides liquid formulations containing xenon dissolved to treat hypoxia and cerebral ischemia.
  • xenon may have an ability to protect organs other than the brain from the consequences of ischemia-reperfusion syndromes, for example to protect the kidney, as described by Ma et al., J Am Soc Nephrol 2009, 20-4: 713-20, or the heart, as taught by Schweibert et al., Eur J Anaesth 2010, Epub.
  • Argon has recently been shown to be effective for the brain, Loetscher et al, Crit.Care 2009, 13: R206
  • the problem is therefore to propose a preventive and / or curative treatment of a peripheral organ deficiency or failure, in particular kidney, heart, liver and lungs, whatever the cause, namely
  • the solution of the invention is then a gaseous composition containing an effective amount of krypton gas of between 15 and 80% by volume for use by inhalation to prevent or to treat a deficiency or failure of at least one peripheral member chosen from liver, kidneys, heart and lungs in a patient.
  • gaseous composition or inhalable gaseous drug of the invention may comprise one or more of the following characteristics:
  • the patient is a human being, especially an adult or a child.
  • the organ deficiency results from an organic and / or functional anomaly.
  • the organ deficiency is transient, preferably less than an hour to several days or weeks, or definitive. it also contains oxygen, preferably at least 21% by volume of oxygen.
  • krypton is administered to the patient one or more times a day for an inhalation duration of a few minutes to one or more hours,
  • - It is formed of a binary gas mixture consisting of krypton and oxygen for the rest or a ternary mixture consisting of krypton, nitrogen and oxygen.
  • the gaseous drug is ready for use.
  • the invention also relates to a use of krypton gas for producing an inhalable drug composition according to the invention for preventing or treating a deficiency or failure of a peripheral organ in a patient.
  • administration of krypton to the patient is by inhalation, for example by means of a ventilator, a nebulizer or spontaneously with pre-conditioned gas bottles, connected to a facial or nasal mask. , or nasal goggles.
  • the duration of administration depends on the duration of the deficiency / failure, chosen on a case by case basis, for example krypton can be administered for a duration of administration of a few minutes to a few tens of minutes, or even hours, by less than one hour, at a frequency of up to one to several times a day and over a total treatment period of one or more days, weeks, months or years ⁇
  • the krypton or gaseous mixture based on krypton is preferentially conditioned by bottle of gas under pressure or in liquid form, for example in a bottle of one to several liters (water capacity), for example from 1 to 50 liters, and at a pressure of between 2 and 300 bar.
  • Krypton or gaseous mixture based on krypton can be in "ready-to-use” form, for example by premixing with oxygen, or it can be mixed on site during its use, in particular with oxygen and optionally another gaseous compound, for example nitrogen.
  • the patient is a human being, that is to say a man or a woman, including children, adolescents or any other group of individuals, for example newborns or infants. old people.
  • the experimental conditions mimicked the cell damage associated with ischemia-reperfusion, via the cytotoxic and antiproliferative effects of staurosporine which is a global tyrosine kinase inhibitor interrupting all trophic signals; rotenone, which is an inhibitor of complex I of the respiratory chain; antimycin A which is a complex III inhibitor of the respiratory chain; menadione which is a redox agent inhibiting the production of oxygen-reactive species on the respiratory chain; and mitoxanthrone which is an anthracycline generating abnormalities of cellular DNA.
  • staurosporine which is a global tyrosine kinase inhibitor interrupting all trophic signals
  • rotenone which is an inhibitor of complex I of the respiratory chain
  • antimycin A which is a complex III inhibitor of the respiratory chain
  • menadione which is a redox agent inhibiting the production of oxygen-reactive species on the respiratory chain
  • mitoxanthrone which is an anthra
  • the cells were maintained in different preservation media, such as medium alone, “free” serum medium, serum medium and “free” nutrient (condition reproducing nutrient depletion and trophic factors), contained medium of rapamycin (positive control of the induction of autophagy) or nocodazole (positive control of stopping cellular mitosis).
  • preservation media such as medium alone, “free” serum medium, serum medium and “free” nutrient (condition reproducing nutrient depletion and trophic factors), contained medium of rapamycin (positive control of the induction of autophagy) or nocodazole (positive control of stopping cellular mitosis).
  • U20S cells are tested and studied under the following conditions:
  • GFP-histone H2B which is a fluorescent green protein generated to mark chromatin and allow monitoring of the cycle of cell division as well as the nuclear condensation of the apoptosis process
  • Red-centrin a red fluorescent protein that labels centrosomes, to measure proliferation and apoptosis in cell culture.
  • GFP-HMGB1 which is a re protein released by the nucleus of the necrotic cells
  • DAPI which allows chromatin labeling to simultaneously evaluate the necrosis, namely the release of GFP-HMGB1, and the apoptosis which is defined by the level of condensation of chromatin, which can be primary, that is to say without releasing of GFP-HMGB1, or secondary, that is to say with release of GFP-HMGB1.
  • GFP-LC3 which is a protein capable of being redistributed: from diffuse to localized punctuate clusters called autophagosomes, when autophagy is induced, in order to measure autophagy.
  • GFP-G3B which is a protein capable of being redistributed: from diffuse to localized punctate clusters called stress granules, when endoplasmic stress (ER) is induced, in order to measure endoplasmic stress (ER).
  • 5-ethyl-2'deoxyuridine which is an analogous thymidine base which is incorporated in the DNA of proliferating cells, revealed by Click-IT-Alexa-Fluor azide which is a molecular probe making it possible to fluoresce the 5-ethyl-2'doxyuridine, and DAPI to study the contents of the DNA.
  • the cells are then analyzed in a BD Pathway Fluorescence Microscope type automaton in order to determine the following parameters:
  • cell cycle defined by the incorporation of 5-ethyl-2'doxyuridine in the cells in phase S, as well as by DNA analysis.
  • the U20S cells were labeled with several fluorochromes determining the functional state of the mitochondria, in particular the tetramethyl rhodamine ester, lipophilic cation measuring the internal transmembrane potential of the mitochondria, the generation of reactive oxygen species, and that is, dehydroethidium, which oxidizes to produce the fluorescent product called ethidium, or the glutathione content, i.e. thiol-reactive fluorochrome monochlorobiman.
  • fluorochromes determining the functional state of the mitochondria, in particular the tetramethyl rhodamine ester, lipophilic cation measuring the internal transmembrane potential of the mitochondria, the generation of reactive oxygen species, and that is, dehydroethidium, which oxidizes to produce the fluorescent product called ethidium, or the glutathione content, i.e. thiol-reactive fluorochrome monochlorobiman.
  • krypton is able to protect these organs, in particular kidney, heart, liver, lungs during acute or chronic, isolated or multiple deficiency, characterized by an organic and / or functional anomaly, transient or permanent is not yet established with certainty.
  • krypton can be used as an inhalable drug to prevent or treat a deficiency or failure of one or more peripheral organs in a patient, in particular the liver, the kidneys, the lungs or heart, whether organ failure is due to localized or generalized infection, localized or generalized acute or chronic inflammation, primary or secondary autoimmune phenomena, trauma, organo-degeneration or another cause.

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Abstract

The invention relates to a gaseous composition containing an effective amount of gaseous krypton for use via inhalation for preventing or treating a deficiency or failure of at least one peripheral organ in a patient. Preferably, it contains between 15 and 80% by volume of krypton and oxygen. The organ deficiency or failure results in particular from an organic or functional anomaly. The organ is chosen from the liver, kidneys, heart and lungs.

Description

Médicament gazeux inhalable à base de krypton contre les déficiences ou défaillance d'organes périphériques  Krypton inhalable gaseous drug against impairments or peripheral organ failure
L'invention porte sur l'utilisation de krypton gazeux pour fabriquer tout ou partie d'un médicament inhalable destiné à traiter ou à prévenir une déficience ou défaillance d'organe, notamment d'un organe choisi parmi le cerveau, les reins, le cœur, le foie et les poumons, que cette déficience soit isolée ou multiple. The invention relates to the use of krypton gas to manufacture all or part of an inhalable medicament for treating or preventing organ deficiency or failure, in particular of an organ selected from the brain, kidneys, heart , the liver and the lungs, whether this deficiency is isolated or multiple.
La déficience ou défaillance d'un organe se caractérise par une anomalie organique et/ou fonctionnelle de l'organe considéré, c'est-à-dire une incapacité ou une impossibilité de cet organe à présenter une fonctionnalité normale.  The deficiency or failure of an organ is characterized by an organic and / or functional abnormality of the organ considered, that is to say an incapacity or an impossibility of this organ to present a normal functionality.
Cette déficience ou défaillance peut être transitoire, c'est-à-dire durer de moins d'une heure à plusieurs jours ou semaines, ou définitive.  This deficiency or failure can be transient, that is to say, last from less than an hour to several days or weeks, or definitive.
La cause d'une déficience ou défaillance d'organe peut être en rapport notamment avec une anomalie/déficit de vascularisation, par exemple l'ischémie-reperfusion, ou d'oxygénation, à une infection localisée ou généralisée, une inflammation aiguë ou chronique localisée ou généralisée, des phénomènes d'auto-immunité primaires ou secondaires, à un traumatisme, à une organo-dégénérescence...  The cause of a deficiency or organ failure can be related in particular to an abnormality / deficit of vascularization, for example the ischemia-reperfusion, or of oxygenation, to a localized or generalized infection, an acute or chronic inflammation localized or generalized, primary or secondary autoimmunity phenomena, trauma, organo-degeneration ...
La déficience ou défaillance peut toucher concomitamment plusieurs organes et on parle alors de déficience multi-organes.  The deficiency or failure can affect several organs concomitantly and one speaks then of multi-organ deficiency.
II est connu de pouvoir traiter certaines déficiences ou défaillance affectant le cerveau à l'aide de gaz inhalés. Ainsi, le document EP-A-1158992 propose d'utiliser du xénon inhalé pour lutter contre les neuro-intoxications cérébrales, notamment ischémiques, qui se caractérisent par un dysfonctionnement cérébral d'un ou de plusieurs systèmes de neurotransmission.  It is known to be able to treat certain deficiencies or failures affecting the brain using inhaled gases. Thus, EP-A-1158992 proposes to use inhaled xenon to fight against cerebral neuro-intoxications, particularly ischemic, which are characterized by cerebral dysfunction of one or more neurotransmission systems.
Par ailleurs, le document EP-A-1541 156 propose quant à lui d'utiliser de l'argon inhalé pour lutter contre lesdites neuro-intoxications cérébrales. Le potentiel neuroprotecteur de l'argon gazeux, administré seul ou en mélange avec du protoxyde d'azote, sur le développement et l'expression de la sensibilisation à la D-amphétamine a également été évalué.  Furthermore, the document EP-A-1541 156 proposes for its part to use inhaled argon to fight against said brain neuro-intoxications. The neuroprotective potential of argon gas, administered alone or in admixture with nitrous oxide, on the development and expression of D-amphetamine sensitization was also evaluated.
Enfin, le document propose l'argon gazeux pour fabriquer tout ou partie d'un médicament inhalable destiné à traiter ou à prévenir une déficience  Finally, the document proposes argon gas to manufacture all or part of an inhalable drug intended to treat or prevent a disability.
Récemment, la capacité de neuroprotection de l'argon a été confirmée par Loetscher et al., Critical Care, 2009, 13 :R206, faisant suite aux travaux sur les cellules cochléaires en culture isolée, c'est-à-dire les cellules dites chevelues issues de l'organe de Corti du rat, comme décrit par Yarin et al., Hear Res 2005, 201 : 1-9. Ces cellules sont assimilables aux neurones cérébraux, pour lesquels d'autres gaz, notamment le xénon, ont été montrés comme pouvant présenter un effet neuroprotecteur, comme rappelé par Ma et al., Br J Anaesth,2002, vol 98: 739-46. En outre, le document EP-A-1651243 propose quant à lui d'utiliser des mélanges Xe/N20 inhalé à cette fin, alors que le document DE-A- 19991033704 propose des formulations liquides contenant du xénon dissout pour traiter les hypoxies et les ischémies cérébrales. Recently, the argon neuroprotective capacity was confirmed by Loetscher et al., Critical Care, 2009, 13: R206, following work on isolated culture cochlear cells, i.e. so-called cells. hairy from the rat's organ of Corti, as described by Yarin et al., Hear Res 2005, 201: 1-9. These cells are comparable to cerebral neurons, for which other gases, in particular xenon, have been shown to have a neuroprotective effect, as recalled by Ma et al., Br J Anaesth, 2002, vol 98: 739-46. In addition, EP-A-1651243 proposes meanwhile to use mixtures Xe / N 2 0 inhaled for this purpose, while the DE-A-19991033704 provides liquid formulations containing xenon dissolved to treat hypoxia and cerebral ischemia.
Comme on le voit, la plupart des traitements proposés visent à traiter des déficiences ou défaillance essentiellement cérébrales, c'est-à-dire qui affectent uniquement le cerveau.  As can be seen, most of the proposed treatments are aimed at treating essentially cerebral impairments or failures, that is, those that affect only the brain.
Cependant, protéger uniquement le cerveau n'est pas suffisant. En effet, il convient également de pouvoir protéger les organes périphériques de toute défaillance, en particulier les organes vitaux comme le cœur, le foie, les reins...  However, protecting only the brain is not enough. Indeed, it should also be possible to protect the peripheral organs from any failure, especially vital organs such as heart, liver, kidneys ...
Des études récentes ont montré que le xénon pouvait avoir une capacité à protéger des organes autres que le cerveau de conséquences de syndromes d'ischémie-reperfusion , par exemple à protéger le rein, comme décrit par Ma et al, J Am Soc Nephrol 2009, 20- 4 :713-20, ou le cœur, comme enseigné par Schweibert et al, Eur J Anaesth 2010, Epub.  Recent studies have shown that xenon may have an ability to protect organs other than the brain from the consequences of ischemia-reperfusion syndromes, for example to protect the kidney, as described by Ma et al., J Am Soc Nephrol 2009, 20-4: 713-20, or the heart, as taught by Schweibert et al., Eur J Anaesth 2010, Epub.
L'argon a été récemment été montré efficace pour le cerveau, Loetscher et al, Crit.Care 2009, 13 :R206  Argon has recently been shown to be effective for the brain, Loetscher et al, Crit.Care 2009, 13: R206
Actuellement, il n'existe pas de médicament réellement efficace permettant de protéger un ou plusieurs organes périphériques, autres que le cerveau, contre une déficience se caractérisant par une anomalie organique ou fonctionnelle de l'organe considéré, c'est-à- dire une incapacité ou une impossibilité de cet organe à présenter une fonctionnalité normale.  Currently, there is no truly effective drug to protect one or more peripheral organs, other than the brain, against a deficiency characterized by an organic or functional abnormality of the organ in question, that is to say a incapacity or impossibility of this organ to present a normal functionality.
Le problème est donc de proposer un traitement préventif et/ou curatif d'une déficience ou défaillance d'organe périphérique, en particulier rein, cœur, foie et poumons, et ce quelle qu'en soit la cause, à savoir  The problem is therefore to propose a preventive and / or curative treatment of a peripheral organ deficiency or failure, in particular kidney, heart, liver and lungs, whatever the cause, namely
La solution de l'invention est alors une composition gazeuse contenant une quantité efficace de krypton gazeux comprise entre 15 et 80 % en volume pour une utilisation par inhalation pour prévenir ou pour traiter une déficience ou défaillance d'au moins un organe périphérique choisi parmi le foie, les reins, le cœur et les poumons chez un patient.  The solution of the invention is then a gaseous composition containing an effective amount of krypton gas of between 15 and 80% by volume for use by inhalation to prevent or to treat a deficiency or failure of at least one peripheral member chosen from liver, kidneys, heart and lungs in a patient.
Selon le cas, la composition gazeuse ou médicament gazeux inhalable de l'invention peut comprendre l'une ou plusieurs des caractéristiques suivantes :  Depending on the case, the gaseous composition or inhalable gaseous drug of the invention may comprise one or more of the following characteristics:
- le patient est un être humain, en particulier un adulte ou un enfant.  - the patient is a human being, especially an adult or a child.
- elle contient au moins 30% en volume de krypton.  - it contains at least 30% by volume of krypton.
- elle contient au moins 40% en volume de krypton.  - it contains at least 40% by volume of krypton.
- elle contient au moins 50% en volume de krypton.  - it contains at least 50% by volume of krypton.
- elle contient moins de 75% en volume de krypton.  - it contains less than 75% by volume of krypton.
- la déficience d'organe résulte d'une anomalie organique et/ou fonctionnelle.  - The organ deficiency results from an organic and / or functional anomaly.
- la déficience d'organe concerne plusieurs organes.  - organ deficiency affects several organs.
- la déficience d'organe est transitoire, de préférence de moins d'une heure à plusieurs jours ou semaines, ou définitive. - elle contient en outre de l'oxygène, de préférence au moins 21% en volume d'oxygène. - The organ deficiency is transient, preferably less than an hour to several days or weeks, or definitive. it also contains oxygen, preferably at least 21% by volume of oxygen.
- elle contient en outre un composé additionnel choisi dans le groupe formé par N20, Xe, Ar, He, Ne, NO, CO, H2S et N2. it furthermore contains an additional compound chosen from the group formed by N 2 O, Xe, Ar, He, Ne, NO, CO, H 2 S and N 2 .
- le krypton est administré au patient, une ou plusieurs fois par jour pendant une durée d'inhalation de quelques minutes à une ou plusieurs heures,  krypton is administered to the patient one or more times a day for an inhalation duration of a few minutes to one or more hours,
- elle est formée d'un mélange gazeux contenant, en outre, de l'oxygène, de l'azote ou leurs mélanges, en particulier de l'air.  - It is formed of a gaseous mixture containing, in addition, oxygen, nitrogen or mixtures thereof, in particular air.
- elle est formée d'un mélange gazeux binaire constitué de krypton et d'oxygène pour le reste ou un mélange ternaire constitué de krypton, d'azote et d'oxygène.  - It is formed of a binary gas mixture consisting of krypton and oxygen for the rest or a ternary mixture consisting of krypton, nitrogen and oxygen.
- le médicament gazeux est prêt à l'emploi.  the gaseous drug is ready for use.
- elle est conditionnée dans une bouteille de gaz.  - it is packaged in a gas bottle.
L'invention porte aussi sur une utilisation de krypton gazeux pour fabriquer une composition médicamenteuse inhalable selon l'invention destinée à prévenir ou à traiter une déficience ou défaillance d'un organe périphérique chez un patient.  The invention also relates to a use of krypton gas for producing an inhalable drug composition according to the invention for preventing or treating a deficiency or failure of a peripheral organ in a patient.
D'une façon générale, lors du traitement, l'administration de krypton au patient se fait par inhalation par exemple au moyen d'un ventilateur, d'un nébuliseur ou spontanément avec des bouteilles de gaz préconditionnées, raccordés à un masque facial ou nasal, ou des lunettes nasales.  In general, during treatment, administration of krypton to the patient is by inhalation, for example by means of a ventilator, a nebulizer or spontaneously with pre-conditioned gas bottles, connected to a facial or nasal mask. , or nasal goggles.
La durée d'administration est fonction de la durée de la déficience / défaillance, choisie au cas par cas, par exemple le krypton peut être administré pendant une durée d'administration de quelques minutes à quelques dizaines de minutes, voire d'heures, par exemple moins d'une heure, à une fréquence pouvant atteindre une à plusieurs fois par jour et sur une durée totale de traitement de un ou plusieurs jours, semaines, mois ou années^ Le krypton ou mélange gazeux à base de krypton est préférentiellement conditionné en bouteille de gaz sous pression ou sous forme liquide, par exemple dans une bouteille d'un à plusieurs litres (contenance en eau), par exemple de 1 à 50 litres, et à une pression comprise entre 2 et 300 bar.  The duration of administration depends on the duration of the deficiency / failure, chosen on a case by case basis, for example krypton can be administered for a duration of administration of a few minutes to a few tens of minutes, or even hours, by less than one hour, at a frequency of up to one to several times a day and over a total treatment period of one or more days, weeks, months or years ^ The krypton or gaseous mixture based on krypton is preferentially conditioned by bottle of gas under pressure or in liquid form, for example in a bottle of one to several liters (water capacity), for example from 1 to 50 liters, and at a pressure of between 2 and 300 bar.
Le krypton ou mélange gazeux à base de krypton peut se présenter sous forme « prêt à l'emploi », par exemple en pré-mélange avec de l'oxygène, ou alors être mélangé sur site lors de son utilisation, notamment avec de l'oxygène et éventuellement un autre composé gazeux, par exemple de l'azote.  Krypton or gaseous mixture based on krypton can be in "ready-to-use" form, for example by premixing with oxygen, or it can be mixed on site during its use, in particular with oxygen and optionally another gaseous compound, for example nitrogen.
Dans le cadre de l'invention, le patient est un être humain, c'est-à-dire un homme ou une femme, y compris les enfants, les adolescents ou tout autre groupe d'individus, par exemple les nouveaux-nés ou les personnes âgées.  In the context of the invention, the patient is a human being, that is to say a man or a woman, including children, adolescents or any other group of individuals, for example newborns or infants. old people.
Exemple  Example
Les essais suivants ont été réalisés pour démontrer que le krypton présente un effet protecteur sur la conservation d'un organe périphérique. Dans cette étude, les effets du krypton gazeux ont été étudiés par la capacité à protéger du phénomène de la mort cellulaire ou apoptose, qui est la conséquence ultime du syndrome d'ischémie-reperfusion que l'on retrouve lors de l'arrêt de la circulation sanguine et au stade ultime celui de la greffe d'organes. The following tests were performed to demonstrate that krypton has a protective effect on the preservation of a peripheral organ. In this study, the effects of gaseous krypton were studied by the ability to protect from the phenomenon of cell death or apoptosis, which is the ultimate consequence of the ischemia-reperfusion syndrome that is found when stopping blood circulation and at the final stage that of organ transplantation.
Afin de réaliser une évaluation de l'efficacité de la protection engendrée par les différents gaz testés, on a examiné leurs capacités à protéger du phénomène de la mort cellulaire ou apoptose.  In order to make an assessment of the effectiveness of the protection generated by the various gases tested, their ability to protect against the phenomenon of cell death or apoptosis was examined.
Les conditions expérimentales mimaient les dégâts cellulaires liées à l'ischémie- reperfusion, via les effets cytotoxiques et antiprolifératifs de la staurosporine qui est un inhibiteur global de la tyrosine kinase interrompant tous les signaux trophiques ; de la rotenone qui est un inhibiteur du complexe I de la chaîne respiratoire; de l'antimycine A qui est un inhibiteur du complexe III de la chaîne respiratoire; la ménadione qui est un agent redox inhibant la production d'espèces oxygène-réactives sur la chaîne respiratoire ; et de la mitoxanthrone qui est une anthracycline générant des anomalies de l'ADN cellulaire.  The experimental conditions mimicked the cell damage associated with ischemia-reperfusion, via the cytotoxic and antiproliferative effects of staurosporine which is a global tyrosine kinase inhibitor interrupting all trophic signals; rotenone, which is an inhibitor of complex I of the respiratory chain; antimycin A which is a complex III inhibitor of the respiratory chain; menadione which is a redox agent inhibiting the production of oxygen-reactive species on the respiratory chain; and mitoxanthrone which is an anthracycline generating abnormalities of cellular DNA.
Les effets ont été évalués à des concentrations proches des doses demi- létales, puis à des doses de 1/10, 1/3, x 3 et x 10.  The effects were assessed at concentrations close to half-lethal doses, then at doses of 1/10, 1/3, x 3 and x 10.
Les cellules étaient maintenues dans différents milieux de conservation, type milieu seul, milieu sérum « free », milieu sérum et nutriment « free » (condition reproduisant la déplétion en nutriments et facteurs trophiques), milieu contenat de la rapamycine (contrôle positif de l'induction de l'autophagie) ou du nocodazole (contrôle positif de l'arrêt de la mitose cellulaire).  The cells were maintained in different preservation media, such as medium alone, "free" serum medium, serum medium and "free" nutrient (condition reproducing nutrient depletion and trophic factors), contained medium of rapamycin (positive control of the induction of autophagy) or nocodazole (positive control of stopping cellular mitosis).
Toutes les expériences ont été menées sous atmosphères gazeuses à base de krypton et autres gaz, tétrappliquées à des fins d'analyse statistique. Les mesures sont réalisées après 6 et 16 heures d'incubation.  All experiments were conducted in gaseous atmospheres based on krypton and other gases, which were applied for statistical analysis purposes. The measurements are carried out after 6 and 16 hours of incubation.
Les cellules U20S sont testées et étudiées dans les conditions suivantes :  U20S cells are tested and studied under the following conditions:
- en présence de GFP-histone H2B qui est une protéine verte en fluorescence générée pour marquer la chromatine et permettre un suivi du cycle de la division cellulaire ainsi que la condensation nucléaire du processus d'apoptose; et de Red-centrin qui est une protéine rouge en fluorescence marquant les centrosomes, afin de mesurer la prolifération et l'apoptose en culture cellulaire.  in the presence of GFP-histone H2B, which is a fluorescent green protein generated to mark chromatin and allow monitoring of the cycle of cell division as well as the nuclear condensation of the apoptosis process; and Red-centrin, a red fluorescent protein that labels centrosomes, to measure proliferation and apoptosis in cell culture.
- en présence de GFP-HMGB1 qui est une protéine re larguée par le noyau des cellules nécrotiques, et de DAPI qui permet un marquage de la chromatine pour évaluer simultanément la nécrose, à savoir le relarguage de GFP-HMGB1, et l'apoptose qui est définit par le niveau de condensation de la chromatine, qui peut être primaire, c'est-à-dire sans relarguage de GFP-HMGB1, ou secondaire, c'est-à-dire avec relarguage de GFP- HMGB1. - en présence de GFP-LC3 qui est une protéine capable de se redistribuer : de diffus à des amas localisés punctiformes dénommés autophagosomes, quand l'autophagie est induite, afin de mesurer l'autophagie. - en présence de GFP-G3B qui est une protéine capable de se redistribuer : de diffus à des amas localisés punctiformes dénommés granules de stress, quand le stress endoplasmique (ER) est induit, afin de mesurer le stress endoplasmique (ER). in the presence of GFP-HMGB1 which is a re protein released by the nucleus of the necrotic cells, and of DAPI which allows chromatin labeling to simultaneously evaluate the necrosis, namely the release of GFP-HMGB1, and the apoptosis which is defined by the level of condensation of chromatin, which can be primary, that is to say without releasing of GFP-HMGB1, or secondary, that is to say with release of GFP-HMGB1. in the presence of GFP-LC3 which is a protein capable of being redistributed: from diffuse to localized punctuate clusters called autophagosomes, when autophagy is induced, in order to measure autophagy. in the presence of GFP-G3B, which is a protein capable of being redistributed: from diffuse to localized punctate clusters called stress granules, when endoplasmic stress (ER) is induced, in order to measure endoplasmic stress (ER).
- en présence de 5-ethyl-2'deoxyuridine qui est une base thymidine analogue qui s'incorpore dans l'ADN de cellules en prolifération, révélée par Click-IT-Alexa-Fluor azide qui est une sonde moléculaire permettant de rendre fluorescent le 5-éthyl-2'doxyuridine, et DAPI afin d'étudier le contenu de l'ADN.  in the presence of 5-ethyl-2'deoxyuridine which is an analogous thymidine base which is incorporated in the DNA of proliferating cells, revealed by Click-IT-Alexa-Fluor azide which is a molecular probe making it possible to fluoresce the 5-ethyl-2'doxyuridine, and DAPI to study the contents of the DNA.
Les cellules sont ensuite analysées dans un automate de type BD Pathway Fluorescence Microscope afin de déterminer les paramètres suivants :  The cells are then analyzed in a BD Pathway Fluorescence Microscope type automaton in order to determine the following parameters:
- apoptose défînite par GFP-H2B ou DAPI-condensation chromatine mesurable), - defined apoptosis by GFP-H2B or DAPI-measurable chromatin condensation,
- autophagie définie par GFP-LC3 puncta, - autophagy defined by GFP-LC3 puncta,
- nécrose définie par l'exsudation de HMGB1 du noyau,  necrosis defined by the exudation of HMGB1 from the nucleus,
- aberrations mitotiques définies par GFP-H2B et Red-Centrin,  mitotic aberrations defined by GFP-H2B and Red-Centrin,
- niveau de stress ER défini par GFP-G3B puncta,  - ER stress level defined by GFP-G3B puncta,
- cycle cellulaire défini par l'incorporation de 5-éthyl-2'doxyuridine dans les cellules en phase S, ainsi que par analyse de l'ADN.  cell cycle defined by the incorporation of 5-ethyl-2'doxyuridine in the cells in phase S, as well as by DNA analysis.
En outre, les cellules U20S ont été marquées avec plusieurs fluorochromes déterminant l'état fonctionnel des mitochondries, en particulier l'ester de tetramethyl rhodamin, cation lipophilique mesurant le potentiel transmembranaire interne de la mitochondrie, la génération d'espèces oxygène réactive, c'est-à-dire du dehydroethidium, qui oxydé génère le produit fluorescent appelé éthidium, ou le contenu en glutathion, c'est- à-dire thiol-reactive f uorochrome monochlorobiman.  In addition, the U20S cells were labeled with several fluorochromes determining the functional state of the mitochondria, in particular the tetramethyl rhodamine ester, lipophilic cation measuring the internal transmembrane potential of the mitochondria, the generation of reactive oxygen species, and that is, dehydroethidium, which oxidizes to produce the fluorescent product called ethidium, or the glutathione content, i.e. thiol-reactive fluorochrome monochlorobiman.
Les résultats obtenus montrent que les cellules conservées sous krypton conformément à l'invention conservent leurs capacités fonctionnelles ainsi que leur intégrité physiques puisque le krypton diminue les signes d'apoptose cellulaire, c'est-à-dire les conséquences lésionnelles lors d'une ischémie-reperfusion.  The results obtained show that the cells stored under krypton in accordance with the invention retain their functional capacities as well as their physical integrity since krypton decreases the signs of cellular apoptosis, that is to say the lesional consequences during ischemia. -reperfusion.
Le mécanisme d'action par lequel le krypton est capable de protéger ces organes, notamment rein, cœur, foie, poumons lors d'une déficience aiguë ou chronique, isolée ou multiple, caractérisée par une anomalie organique et/ou fonctionnelle, transitoire ou définitive n'est pas encore établi avec certitude.  The mechanism of action by which krypton is able to protect these organs, in particular kidney, heart, liver, lungs during acute or chronic, isolated or multiple deficiency, characterized by an organic and / or functional anomaly, transient or permanent is not yet established with certainty.
Malgré cela, les résultats obtenus lors de ces essais montrent clairement que le krypton peut être utilisé en tant que médicament inhalable pour prévenir ou traiter une déficience ou défaillance d'un ou plusieurs organes périphériques chez un patient, en particulier le foie, les reins, les poumons ou le cœur, que la défaillance d'organe soit due à une infection localisée ou généralisée, une inflammation aiguë ou chronique localisée ou généralisée, des phénomènes d'auto-immunité primaires ou secondaires, à un traumatisme, à une organo-dégénérescence ou une autre cause.  Despite this, the results obtained during these tests clearly show that krypton can be used as an inhalable drug to prevent or treat a deficiency or failure of one or more peripheral organs in a patient, in particular the liver, the kidneys, the lungs or heart, whether organ failure is due to localized or generalized infection, localized or generalized acute or chronic inflammation, primary or secondary autoimmune phenomena, trauma, organo-degeneration or another cause.

Claims

Revendications claims
1. Composition gazeuse contenant une quantité efficace de krypton gazeux en une proportion volumique comprise entre 15 et 80 % pour une utilisation par inhalation pour prévenir ou pour traiter une déficience ou défaillance d'au moins un organe périphérique choisi parmi le foie, les reins, le cœur et les poumons chez un patient. A gaseous composition containing an effective amount of krypton gas in a volume proportion of between 15 and 80% for inhalation use for preventing or treating a deficiency or failure of at least one peripheral organ selected from the liver, kidneys, heart and lungs in a patient.
2. Composition selon la revendication précédente, caractérisée en ce qu'elle contient au moins 30% en volume de krypton. 2. Composition according to the preceding claim, characterized in that it contains at least 30% by volume of krypton.
3. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle contient moins de 75% en volume de krypton. 3. Composition according to one of the preceding claims, characterized in that it contains less than 75% by volume of krypton.
4. Composition selon l'une des revendications précédentes, caractérisée en ce que la déficience ou défaillance d'organe résulte d'une anomalie organique et/ou fonctionnelle. 4. Composition according to one of the preceding claims, characterized in that the deficiency or organ failure results from an organic and / or functional anomaly.
5. Composition selon l'une des revendications précédentes, caractérisée en ce que la déficience ou défaillance d'organe concerne plusieurs organes. 5. Composition according to one of the preceding claims, characterized in that the deficiency or organ failure concerns several organs.
6. Composition selon l'une des revendications précédentes, caractérisée en ce que la déficience ou défaillance d'organe est transitoire, en particulier de moins d'une heure à plusieurs jours ou semaines, ou définitive. 6. Composition according to one of the preceding claims, characterized in that the deficiency or organ failure is transient, in particular less than an hour to several days or weeks, or final.
7. Composition selon la revendication 6, caractérisée en ce que le krypton est administré au patient, une ou plusieurs fois par jour pendant une durée d'inhalation de quelques minutes à une ou plusieurs heures. 7. Composition according to claim 6, characterized in that krypton is administered to the patient, one or more times a day for an inhalation time of a few minutes to one or more hours.
8. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle contient en outre de l'oxygène, de préférence au moins 21% en volume d'oxygène. 8. Composition according to one of the preceding claims, characterized in that it further contains oxygen, preferably at least 21% by volume of oxygen.
9. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle contient en outre un composé additionnel choisi dans le groupe formé par N20, Xe, Ar, He, Ne, NO, CO, H2S et N2. 9. Composition according to one of the preceding claims, characterized in that it further contains an additional compound selected from the group consisting of N 2 0, Xe, Ar, He, Ne, NO, CO, H 2 S and N 2 .
10. Composition selon l'une des revendications précédentes, caractérisée en ce que le patient est un être humain. 10. Composition according to one of the preceding claims, characterized in that the patient is a human being.
PCT/FR2011/051112 2010-06-08 2011-05-18 Krypton-based inhalable gaseous medicinal product for combatting deficiencies or failure of peripheral organs WO2011154630A1 (en)

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