WO2010035074A1 - Utilisation d'oxyde de diazote, d'argon, de xénon, d'hélium ou de néon pour fabriquer une composition pharmaceutique destinée à traiter des lésions ischémiques chez des patients ne pouvant pas être traités par des agents thrombolytiques - Google Patents

Utilisation d'oxyde de diazote, d'argon, de xénon, d'hélium ou de néon pour fabriquer une composition pharmaceutique destinée à traiter des lésions ischémiques chez des patients ne pouvant pas être traités par des agents thrombolytiques Download PDF

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Publication number
WO2010035074A1
WO2010035074A1 PCT/IB2008/055624 IB2008055624W WO2010035074A1 WO 2010035074 A1 WO2010035074 A1 WO 2010035074A1 IB 2008055624 W IB2008055624 W IB 2008055624W WO 2010035074 A1 WO2010035074 A1 WO 2010035074A1
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xenon
argon
helium
nitrous oxide
advantageously
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PCT/IB2008/055624
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English (en)
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Jacques Abraini
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Nnoxe Pharmaceutiques Inc
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Priority to PCT/IB2008/055624 priority Critical patent/WO2010035074A1/fr
Publication of WO2010035074A1 publication Critical patent/WO2010035074A1/fr

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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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

  • 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
  • the present invention relates to a method for treating ischemic insults in patients who cannot be treated with thrombolytic agents, especially in humans or animals.
  • the present invention relates to the use of at least one gas selected from the group consisting of nitrous oxide, argon, xenon, helium, neon, and mixtures thereof, for the manufacture of a pharmaceutical composition for treating ischemic insults such as, but not limited to, cerebral ischemia, cardiac ischemia, renal ischemia, retinal ischemia, or lower limb's ischemia, in patients who cannot be treated or are not treated with a thrombolytic agent, such as the human recombinant form of tissue-type plasminogen activator (rt-PA).
  • rt-PA tissue-type plasminogen activator
  • Ischemia is a restriction in blood supply generally due to factors in the blood vessels, particularly thromboembolism (blood clots), which lead to tissue dysfunction and cell death through necrotic and apoptotic mechanisms.
  • Ischemia is an absolute or relative shortage of the blood supply to an organ. Relative shortage means the mismatch of blood supply and blood request for adequate oxygen (and glucose) delivery in tissue.
  • the extent of tissue damage mainly depends on the level and duration of ischemia.
  • the heart, the kidneys, and the brain are among the organs that are the most sensitive to inadequate blood supply. For instance, ischemic stroke (also called brain attack or acute cerebral ischemia) and myocardial infarction (also called heart attack or acute cardiac ischemia) are with cancer the major causes of death in humans.
  • Acute cerebral ischemia is caused by a reduction of blood flow in the brain because of the production of a fibrin (blood) clot. This leads more or less to brain dysfunctions and damage and neuronal death.
  • the extent of brain injury mainly depends on the level and duration of ischemia.
  • the physiological processes involved in ischemia-induced neuronal death are complex. Briefly, the reduction in cerebral blood flow compromises tissue energy stores and leads to a deficit in oxygen and glucose. At the cellular level, a critical consequence of this metabolic deprivation is an increase of the intracellular sodium concentration. This leads to an exaggerated efflux and uptake failure of many neurotransmitters, among them is glutamate (Dirnagl et al, Trends Neurosci. 22: 391, 1999).
  • NMDA N-methyl- D-aspartate
  • Fibrinolysis is a particular case of proteolysis.
  • Proteolysis can be defined as the directed (oriented) degradation of proteins by cellular enzymes called proteases through catalytic processes.
  • Fibrinolysis is the physiological process wherein a fibrin (blood) clot is broken down. This occurs through endothelial cells that release a serine protease called tissue-type plasminogen activator (t-PA) that converts the proenzyme plasminogen to plasmin, the main enzyme of fibrin, which cuts the fibrin mesh. In healthy subjects, this process allows avoiding excessive clot formation and ischemic accidents.
  • tissue-PA tissue-type plasminogen activator
  • fibrinolysis may allow individuals to break down endogenously a fibrin (blood) clot. Fibrinolysis can be also stimulated exogenously through administration of analogs of tissue-type plasminogen activator, such as the human recombinant form of tissue-type plasminogen activator (rt-PA). Exogenously-stimulated fibrinolysis is generally called thrombolysis.
  • tissue-type plasminogen activator such as the human recombinant form of tissue-type plasminogen activator (rt-PA).
  • Exogenously-stimulated fibrinolysis is generally called thrombolysis.
  • Today, the intravenous or intra-arterial injection of rt-PA is the only therapy approved by the Food and Drug Administration and the European Medical Agencies for treating ischemic stroke, i.e. acute cerebral ischemia.
  • thrombolytic therapy is associated with a risk of hemorrhagic transformation and neuronal death potentiation that is due to the general proteolytic properties of plasmin (Tsirka et al, Nature, 377: 340-344, 1995; Wang et al., Nature Med., 4: 228-231, 1998; Kaur et al., J. Cereb. Blood Flow Metab. 24: 945, 2004).
  • rt-PA has to be administered to the patient within an appropriate period, called "therapeutic window", typically of up to 3 hours following the occurrence of the symptoms induced by ischemia according to the current medical practice and knowledge.
  • thrombolysis therapy is restricted to about only 5% of the patients suffering ischemic insults, those who can be treated within an appropriate therapeutic window.
  • blockade of the neurotoxic cascade initiated by glutamate by the use of NMDA glutamate receptor antagonists yet has not been proven being efficient in humans, because prototypical (high-affinity) NMDA receptor antagonists possess an intrinsic behavioral toxicity, which is believed to be related to the occurrence of vacuolizations in neurons of the posterior cingulated and retro-splenial cortices (Olney et al., Science, 244:1360, 1989; 254: 1515, 1991; Davis et al., Stroke, 31 :347, 2000).
  • Argon, helium, and neon have also been shown to be neuroprotective (Yarin et al., Hear Res., 201 :1, 2005; Pan et al., Exp Neurol, 205:587, 2007; Pagel et al., Anesth Analg., 105:562, 2007).
  • neuroprotective properties of nitrous oxide, xenon and argon have been patented. See for instance U.S.
  • Patents n° 6,274,633 and 6,653,354 which relate to the use of xenon as an NMDA antagonist, in particular for providing neuroprotection, or European patent EP 1 158 992, which teaches the use of xenon or of a mixture of xenon and oxygen, nitrogen or air, to treat neurointoxications. See also French patent FR 2 863 169, which relates to the use of argon or of gas mixtures containing argon for treating neurointoxications.
  • the inventors discovered that the neuroprotective gases nitrous oxide, xenon, argon, helium, neon, and mixtures thereof, when administered at specific concentration ranges, inhibit the catalytic activity of t-PA and plasmin and further block or reduce thrombolysis and blood flow reperfusion.
  • those neuroprotective gases and mixtures thereof when given at different concentration ranges than those that inhibit the t-PA-plasmin pathway, do not alter the catalytic activity of t-PA and plasmin, and thus do not block or reduce thrombolysis and blood flow reperfusion.
  • the present invention thus relates to a method for providing neuroprotection for the treatment of ischemia in humans or animals, i.e.
  • the neuroprotective gases selected from nitrous oxide, xenon, argon, helium, neon, and mixtures thereof.
  • the present invention relates to the use of at least one gas selected from the group consisting of nitrous oxide, argon, xenon, helium, neon, and mixtures thereof, for the manufacture of a pharmaceutical composition for treating ischemic insults in patients who cannot be treated on time with thrombolytic agents, such as rt-PA, or in patients who are not treated with thrombolytic agents.
  • thrombolytic agents such as rt-PA
  • the pharmaceutical composition is for treating ischemic insults such as, but not limited to, cerebral ischemia, cardiac ischemia, renal ischemia, retinal ischemia, or lower limb's ischemia.
  • ischemic insults such as, but not limited to, cerebral ischemia, cardiac ischemia, renal ischemia, retinal ischemia, or lower limb's ischemia.
  • said at least one gas is administered to patients at concentrations that do not block, reduce or inhibit fibrinolysis.
  • said at least one gas is administered advantageously to patients who cannot be treated with thrombolytic agents, in order to provide neuroprotection without blocking, reducing or inhibiting fibrinolysis.
  • the pharmaceutical composition of the present invention comprises only one gas selected from nitrous oxide, xenon, argon, helium, and neon.
  • the gas is xenon in a volume proportion between 1 % and 40 %, more advantageously between 1 % and 35 %, more advantageously between 10 % and 35 %, most advantageously between 15 % and 25 %.
  • the gas is nitrous oxide in a volume proportion between 1 % and 40 %, more advantageously between 1 % and 35 %, more advantageously between 10 % and 35 %, more advantageously between 15 % and 35 %, most advantageously between 20 % and 30 %.
  • the gas is helium in a volume proportion between 1 % and 40 %, more advantageously between 1 % and 35 %, more advantageously between 10 % and 35 %, more advantageously between 15 and 35 %, most advantageously between 25 % and 30 %.
  • the gas is neon in a volume proportion between 1 % and 40 %, more advantageously between 1 % and 35 %, more advantageously between 10 % and 35 %, more advantageously between 15 and 35 %, most advantageously between 25 % and 30 %.
  • the gas is argon in a volume proportion between 46 % and 99 %, more advantageously between 50 % and 80 %, most advantageously between 50 % and 75 %.
  • the pharmaceutical composition of the present invention comprises a mixture of gases selected from nitrous oxide, xenon, argon, helium, and neon.
  • it comprises a mixture of two gases selected from nitrous oxide, xenon, argon, helium, and neon.
  • Gases are in equimolar or non-equimolar volume proportions.
  • the gas mixture is a mixture of xenon and nitrous oxide, the volume proportion of xenon being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %, and the volume proportion of nitrous oxide being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %.
  • the gas mixture is a mixture of xenon and helium, the volume proportion of xenon being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %, and the volume proportion of helium being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %.
  • the gas mixture is a mixture of xenon and argon, the volume proportion of xenon being between 1 % and 50 %, more advantageously between 5 % and 25 %, most advantageously between 10 % and 15 %, and the volume proportion of argon being between 1 % and 25 %, more advantageously between 5 % and 25 %, most advantageously between 10 % and 15 %.
  • the gas mixture is a mixture of nitrous oxide and argon, the volume proportion of nitrous oxide being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %, and the volume proportion of argon being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %.
  • the gas mixture is a mixture of nitrous oxide and helium, the volume proportion of nitrous oxide being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %, and the volume proportion of helium being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %.
  • the gas mixture is a mixture of helium and argon, the volume proportion of helium being between 1 % and 50 %, more advantageously between 5 % and 30 %, most advantageously between 10 % and 20 %, and the volume proportion of argon being between 1 % and 50 %, more advantageously between 5 % and 30 %, most advantageously between 10 % and 20 %.
  • the gas mixture is a mixture of xenon and neon, the volume proportion of xenon being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %, and the volume proportion of neon being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %.
  • the gas mixture is a mixture of nitrous oxide and neon, the volume proportion of nitrous oxide being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %, and the volume proportion of neon being between 1 % and 40 %, more advantageously between 5 % and 20 %, most advantageously between 5 % and 10 %.
  • the gas mixture is a mixture of neon and argon, the volume proportion of neon being between 1 % and 50 %, more advantageously between 5 % and 30 %, most advantageously between 10 % and 20 %, and the volume proportion of argon being between 1 % and 50 %, more advantageously between 5 % and 30 %, most advantageously between 10 % and 20 %.
  • the remainder of gases is oxygen alone or oxygen completed with nitrogen.
  • the volume proportion of oxygen is comprised between 18 vol% and 30 vol%, more advantageously between 21 vol% and 25 vol%.
  • At least one gas selected from the group consisting of nitrous oxide, xenon, argon, helium, neon, and mixtures thereof, is administered to the patient.
  • said at least one gas can be administered at the same concentration as before (see above) or, if necessary, can be given at other concentrations advantageously in order to increase neuroprotection.
  • only one gas selected from nitrous oxide, xenon, helium, and neon is administered at the same concentration as before (see above) or, if necessary, is administered advantageously at higher concentrations to increase neuroprotection.
  • the gas is xenon in a volume proportion between 30 % and 99 %, more advantageously between 36 % and 99 %, more advantageously between 40 % and 80 %, most advantageously between 35 % and 50 %.
  • the gas is nitrous oxide in a volume proportion between 30 % and 99 %, more advantageously between 36 % and 99 %, more advantageously between 40 % and 80 %, most advantageously between 35 % and 50 %.
  • the gas is helium in a volume proportion between 30 % and 99 %, more advantageously between 36 % and 99 %, more advantageously between 40 % and 80 %, more advantageously between 50 and 80 %, most advantageously between 50 % and 75 %.
  • the gas is neon in a volume proportion between 30 % and 99 %, more advantageously between 36 % and 99 %, more advantageously between 40 % and 80 %, more advantageously between 50 and 80 %, most advantageously between 50 % and 75 %.
  • argon is administered at the same concentration as before (see above) or, if necessary, is given at lower concentrations in order to increase neuroprotection.
  • the gas is argon in a volume proportion between 1 % and 45 %, more advantageously between 10 % and 40 %, more advantageously between 15 % and 40 %, most advantageously between 25 % and 35 %.
  • a mixture of gases selected from nitrous oxide, xenon, argon, helium, and neon is administered to the patient.
  • it comprises a mixture of two gases selected from nitrous oxide, xenon, argon, helium, and neon, wherein gases are at the same concentration as before (see above), or, if necessary, are given at higher concentrations in order to increase neuroprotection.
  • gases are in equimolar or non-equimolar volume proportions.
  • the gas mixture is a mixture of xenon and nitrous oxide, the volume proportion of xenon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of nitrous oxide being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the gas mixture is a mixture of xenon and helium, the volume proportion of xenon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of helium being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the gas mixture is a mixture of xenon and argon, the volume proportion of xenon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 20 % and 35 %, and the volume proportion of argon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 20 % and 35 %.
  • the gas mixture is a mixture of nitrous oxide and argon, the volume proportion of nitrous oxide being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of argon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the gas mixture is a mixture of nitrous oxide and helium, the volume proportion of nitrous oxide being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of helium being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the gas mixture is a mixture of helium and argon, the volume proportion of helium being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of argon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the gas mixture is a mixture of xenon and neon, the volume proportion of xenon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of neon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the gas mixture is a mixture of nitrous oxide and neon, the volume proportion of nitrous oxide being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of neon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the gas mixture is a mixture of neon and argon, the volume proportion of neon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %, and the volume proportion of argon being between 1 % and 80 %, more advantageously between 10 % and 40 %, most advantageously between 15 % and 35 %.
  • the remainder of gases is oxygen alone or oxygen completed with nitrogen.
  • the volume proportion of oxygen is comprised between 18 vol% and 30 vol%, more advantageously between 21 vol% and 25 vol%.
  • the delay is comprised between 5 and 180 min (3 h), more advantageously between 60 and 180 min, most advantageously between 120 and 180 min, after reperfusion has occurred (i.e. once blood flow has been restored).
  • At least one gas selected from the neuroprotective gases nitrous oxide, xenon, argon, helium, neon, and mixtures thereof is first administered to the patient at concentrations that do not block or reduce fibrinolysis, advantageously within an appropriate therapeutic window following the occurrence of the symptoms of ischemia. Then, once blood flow has been restored, said at least one gas or a mixture of gases selected from the neuroprotective gases nitrous oxide, xenon, argon, helium, and neon can be administered at the same concentration as before or, if necessary as described above, can be given at other concentrations in order to increase neuroprotection, advantageously with an appropriate delay in order not to favor re-occlusion.
  • said at least one gas selected from the neuroprotective gases nitrous oxide, xenon, argon, helium, neon, and mixtures thereof is administered simultaneously, separately or sequentially with at least one other drug and/or any particular condition possessing or not neuroprotective properties by itself, which may enhance, increase, or potentiate the neuroprotective action of said at least one gas.
  • Said at least one gas is thus advantageously administered before, together with, and/or after said at least one other drug and/or any particular condition.
  • Such drugs can be for instance, but are not limited to, alpha(2)-adrenoceptor agonists, such as dexmedetomidine (Rajakumaraswamy et al, Neurosci Lett. 409:128, 2006), carbon monoxide, nitric oxide, garlic extracts or other natural compound extracts, and/or hydrogen which is a gas shown to possess therapeutic antioxidant properties (Osawa et al., Nature Med. 13:688, 2007).
  • carbon monoxide or nitric oxide is administered at concentrations of a few ppm.
  • hydrogen is administered in a volume proportion of 0.5 to 4.7 %.
  • said at least one gas selected from the neuroprotective gases nitrous oxide, xenon, argon, helium and neon, and mixtures thereof is intended for inhalable administration, such as oral inhalation or nasal inhalation, or any other appropriate route of administration. If inhaled, the pharmaceutical composition according to the invention is administered to the patient via his upper respiratory pathways, i.e.
  • any suitable administration device comprising a patient respiratory interface, such as a respiratory mask or a tracheal probe, one or more feed pipes serving to convey the gaseous pharmaceutical composition from a source containing the said pharmaceutical composition to the interface, and a regulator and/or a medical or an anesthesia ventilator serving to deliver and/or extract the patient's respiratory gas.
  • a patient respiratory interface such as a respiratory mask or a tracheal probe
  • feed pipes serving to convey the gaseous pharmaceutical composition from a source containing the said pharmaceutical composition to the interface
  • a regulator and/or a medical or an anesthesia ventilator serving to deliver and/or extract the patient's respiratory gas.
  • FIGURE 1 illustrates the inhibiting effect of various concentrations of gases selected from nitrous oxide, xenon, helium, and argon on the catalytic activity of t-PA.
  • Figure 1 A to 1 C shows the inhibiting effect of various concentrations of nitrous oxide (Fig. 1 A), xenon (Fig. 1 B), and helium (Fig. 1C) on the catalytic activity of t-PA.
  • Figure 1 D shows the effects of xenon, argon, and helium at 75 vol% on the catalytic activity of plasmin.
  • Figure 1 E shows the effects of various gas mixtures containing xenon, nitrous oxide, helium, and/or argon at various concentrations on the catalytic activity of t-PA.
  • Figure 2 illustrates the inhibiting effect of xenon on fibrinolysis in vivo in rats subjected to middle cerebral artery occlusion using an autologous blood clot.
  • EXAMPLE 1 EFFECT OF VARIOUS CONCENTRATIONS OF NITROUS OXIDE, XENON, ARGON, AND HELIUM ON THE CATALYTIC ACTIVITY OF T-PA AND PLASMIN EX VIVO (FIGURE 1).
  • Solutions of t-PA or plasmin and their substrates were saturated with air (control), or with nitrous oxide, argon, xenon, or helium at concentrations of 15 vol% to 75 vol%, the remainder being oxygen at 25 vol%, completed with nitrogen when necessary.
  • Figure 1 A to 1 C shows the inhibiting effect of various concentrations of nitrous oxide (Fig. 1 A), xenon (Fig. 1 B), and helium (Fig. 1C) on the catalytic activity of t-PA.
  • Figure 1 D shows the effects of xenon, argon, and helium at 75 vol% on the catalytic activity of plasmin.
  • Figure 1 E shows the effects of various gas mixtures containing xenon, nitrous oxide, helium, and/or argon at various concentrations on the catalytic activity of t-PA. Similar results were obtained with neon (data not shown).
  • t-PA and plasmin can be reduced by nitrous oxide, xenon, argon, neon, helium, and mixtures thereof when given at specific concentration ranges.
  • EXAMPLE 2 EFFECTS OF XENON ON FIBRINOLYSIS IN VIVO (FIGURE 2)

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Abstract

L'invention concerne l'utilisation d'au moins un gaz sélectionné dans le groupe constitué par l'oxyde de diazote, l'argon, le xénon, l'hélium ou le néon et des mélanges de ceux-ci, pour fabriquer une composition pharmaceutique destinée à traiter des lésions ischémiques chez des patients ne pouvant pas être traités par des agents thrombolytiques, tels que la forme recombinée humaine de l'activateur du plasminogène de type tissu (rt-PA).
PCT/IB2008/055624 2008-09-25 2008-09-25 Utilisation d'oxyde de diazote, d'argon, de xénon, d'hélium ou de néon pour fabriquer une composition pharmaceutique destinée à traiter des lésions ischémiques chez des patients ne pouvant pas être traités par des agents thrombolytiques WO2010035074A1 (fr)

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FR2975597A1 (fr) * 2011-05-24 2012-11-30 Air Liquide Utilisation de neon pour le traitement des neuro-intoxications, notamment des maladies enurodegeneratives et demyelinisantes
FR2975598A1 (fr) * 2011-05-24 2012-11-30 Air Liquide Medicament gazeux inhalable a base de neon pour lutter contre les deficiences d'organes
RU2475249C1 (ru) * 2011-10-05 2013-02-20 Учреждение Российской академии медицинских наук Научно-исследовательский институт фармакологии Сибирского отделения РАМН Средство для наружной терапии хронических рецидивирующих воспалительных заболеваний кожи
US9332474B2 (en) 2012-05-17 2016-05-03 Telefonaktiebolaget L M Ericsson Signaling support for multi sector deployment in cellular communications
US20160199406A1 (en) * 2013-08-19 2016-07-14 Klaus Michael SCHMIDT Non-anesthetic protective gases in combination with liquid anesthetic agents for organ protection
FR3049862A1 (fr) * 2016-04-08 2017-10-13 Monatomics Tech Composition gazeuse inhalable thermiquement neutre
FR3049863A1 (fr) * 2016-04-08 2017-10-13 Monatomics Tech Composition gazeuse inhalable hypothermique
EP3424550A1 (fr) * 2017-07-06 2019-01-09 Monatomics Technology Des mélanges gazeux contenant de faibles concentrations de xénon et de le argon assurer une neuroprotection sans inhiber le activité catalytique d'agents thrombolytiques
EP3424490A1 (fr) * 2017-07-06 2019-01-09 Monatomics Technology Mélanges de gaz contenant du xénon, le argon à faible concentration en tant qu'agent protecteur d'organisme, en particulier de neuroprotecteur
US20210077767A1 (en) * 2019-09-12 2021-03-18 L'Air Liquide, Société Anonyme pour l'Etude et l'Exploitation des Procédés Georges Claude Argon combined with thrombectomy in the event of ischaemic stroke
US11052106B2 (en) 2016-04-08 2021-07-06 Monatomics Technology Hypothermal inhalation gas composition

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FR2975597A1 (fr) * 2011-05-24 2012-11-30 Air Liquide Utilisation de neon pour le traitement des neuro-intoxications, notamment des maladies enurodegeneratives et demyelinisantes
FR2975598A1 (fr) * 2011-05-24 2012-11-30 Air Liquide Medicament gazeux inhalable a base de neon pour lutter contre les deficiences d'organes
RU2475249C1 (ru) * 2011-10-05 2013-02-20 Учреждение Российской академии медицинских наук Научно-исследовательский институт фармакологии Сибирского отделения РАМН Средство для наружной терапии хронических рецидивирующих воспалительных заболеваний кожи
US9332474B2 (en) 2012-05-17 2016-05-03 Telefonaktiebolaget L M Ericsson Signaling support for multi sector deployment in cellular communications
US20160199406A1 (en) * 2013-08-19 2016-07-14 Klaus Michael SCHMIDT Non-anesthetic protective gases in combination with liquid anesthetic agents for organ protection
FR3049862A1 (fr) * 2016-04-08 2017-10-13 Monatomics Tech Composition gazeuse inhalable thermiquement neutre
FR3049863A1 (fr) * 2016-04-08 2017-10-13 Monatomics Tech Composition gazeuse inhalable hypothermique
US11052106B2 (en) 2016-04-08 2021-07-06 Monatomics Technology Hypothermal inhalation gas composition
EP3424490A1 (fr) * 2017-07-06 2019-01-09 Monatomics Technology Mélanges de gaz contenant du xénon, le argon à faible concentration en tant qu'agent protecteur d'organisme, en particulier de neuroprotecteur
WO2019008015A1 (fr) * 2017-07-06 2019-01-10 Monatomics Technology Mélanges gazeux contenant du xénon et de l'argon à faible concentration en tant qu'agent protecteur d'organe, en particulier neuroprotecteur
WO2019008014A1 (fr) * 2017-07-06 2019-01-10 Monatomics Technology Mélanges de gaz contenant de faibles concentrations de xénon et d'argon fournissent une neuroprotection sans inhiber l'activité catalytique d'agents thrombolytiques
CN111093748A (zh) * 2017-07-06 2020-05-01 单原子技术公司 含有低浓度氙和氩的气体混合物提供神经保护作用而不抑制血栓溶解剂的催化活性
JP2020525511A (ja) * 2017-07-06 2020-08-27 モナトミクス テクノロジー 低濃度のキセノンおよびアルゴンを含有するガス混合物は血栓溶解剤の触媒活性を阻害することなく神経保護を提供する
EP3424550A1 (fr) * 2017-07-06 2019-01-09 Monatomics Technology Des mélanges gazeux contenant de faibles concentrations de xénon et de le argon assurer une neuroprotection sans inhiber le activité catalytique d'agents thrombolytiques
US20210077767A1 (en) * 2019-09-12 2021-03-18 L'Air Liquide, Société Anonyme pour l'Etude et l'Exploitation des Procédés Georges Claude Argon combined with thrombectomy in the event of ischaemic stroke
US11717635B2 (en) * 2019-09-12 2023-08-08 L'Air Liquide, SociétéAnonyme pour l'Etude et l'Exploitation des Procédés Georges Claude Argon combined with thrombectomy in the event of ischaemic stroke

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