FR3123803A3 - Gas mixture usable in case of ischemic stroke - Google Patents

Abstract

Title of the invention Gas mixture usable in case of ischemic stroke The invention relates to an inhalable gaseous medicine containing argon, nitrogen and oxygen gas, such as a ternary mixture, for use in to treat, attenuate or resorb cerebral lesions consecutive to an ischemic cerebrovascular accident (CVA) in an individual undergoing a mechanical thrombectomy, with or without thrombolysis. Abstract Figure: None

Description

Gas mixture usable in case of ischemic stroke

The present invention relates to an inhalable gaseous drug containing argon (Ar), oxygen (O ₂ ) and nitrogen (N ₂ ), in particular a ternary Ar/O ₂ /N ₂ mixture, c' is, consisting of argon, oxygen and nitrogen, for use in conjunction with mechanical thrombectomy to treat, alleviate or reverse brain damage resulting from ischemic stroke (CVA) in an individual, ie a patient.

Ischemic stroke or AVCi is a major cause of morbidity and mortality. In addition, neurological and functional recovery after stroke is often incomplete. Thus, after 1 year, half of the survivors suffer from various degrees of motor or mental pathologies. Stroke is the leading cause of disability in adults worldwide and the third leading cause of death.

The majority of strokes are due to a blood clot that clogs a blood vessel in a person's brain, which blocks blood flow, thus irrigation and oxygenation of a brain region, leading to weakening and then the death of neurons in the non-irrigated zone.

This damage occurs immediately during the stroke but also after the stroke, i.e. it extends during the following hours and days despite the resolution of the clot by mechanical thrombectomy, i.e. i.e. mechanical extraction of the clot, by thrombolytic agents causing pharmacological dissolution of the clot, or by these two methods associated with each other.

Mechanical thrombectomy, by allowing rapid removal of the blood clot, has greatly improved post-stroke prognosis compared to thrombolysis alone. However, less than half of the patients come out with a clinical score allowing them to live independently 90 days after the stroke, and a large majority of them suffer from sequelae, or even die as a result of the treatment.

All current stroke treatments aim to restore brain flow. In other words, none of the existing treatments treats brain cells weakened by the consequences of stroke, in particular lack of oxygenation, inflammation, edema, oxidative stress, etc.

In addition, there are studies on the protective effects of argon on different in vitro and in vivo models of brain cell aggression. However, those which have studied the effects of exposure to argon in the context of cerebral ischemia, have been carried out in experimental models of rodents which weakly reproduce the human conditions of ischemic stroke and which have never given rise to any medicine placed on the market.

This is explained by the fact that these rodent models have shown their limits in reproducing brain function and human pathology. Indeed, the structural and functional differences between a human brain and a rodent brain are too great and, in fact, to date, no treatment of cells weakened by cerebral ischemia having demonstrated an effect in rodents has seen its effect reproduce in humans. In other words, the observations made in rodents cannot be transposed to humans in this pathology, in particular with regard to the precise methods of use and dosage of a new treatment.

EP-A-3424550 teaches a gas mixture containing 5 to 20% argon, 5 to 20% xenon (% by vol.) and one or more other constituents, namely oxygen, nitrogen, helium or neon, for restore blood flow in a patient, especially in the event of a thrombectomy which may or may not be induced.

EP-A-1541156 proposes to use argon or different argon-based gas mixtures to fight against neuro-intoxications by acting on brain receptors to regulate the functioning of dopamine, glutamate, serotonin neurotransmission systems , acetylcholine, taurine, GABA or norepinephrine. The examples given show an effect against amphetamine addiction.

Furthermore, EP-A-3791886 proposes a binary inhalable gas mixture (Ar/O ₂ ) consisting of argon and oxygen for use in association with mechanical thrombectomy to treat, attenuate or resorb cerebral lesions following a stroke. in a patient. The concentration by volume of argon is between 30 and 79 vol.% and that of oxygen is between 21 and 70 vol.%. However, high oxygen levels can lead to overoxygenation in some patients.

In view of this, a problem is to be able to improve the treatment of ischemic cerebral vascular accidents (AVCi) in humans, i.e. a patient, so as to treat, attenuate or resorb cerebral lesions consecutive to such an AVCi but without sur - oxygenate the patient.

A solution according to the invention relates to an inhalable gaseous drug containing argon (Ar), oxygen (O ₂ ) and nitrogen (N ₂ ) for use in treating, attenuating or reversing consequential brain damage to an ischemic cerebrovascular accident (AVCi) in an individual undergoing mechanical thrombectomy, the volume proportion of argon being between 30 and 70%, the volume proportion of oxygen being at least 21% and the volume proportion of nitrogen being between 9 and 42% (% by vol).

In the context of the invention, the proportions of the various compounds are proportions by volume (i.e.% by vol), abbreviated "vol.%" or more simply "%".

In other words, the Ar/O ₂ /N ₂ inhalable gaseous drug of the invention is intended to be used in association with a mechanical thrombectomy to treat, attenuate or resorb cerebral lesions consecutive to an ischemic cerebrovascular accident (AVCi) in a individual, ie a human being,

In other words, the invention therefore relates to an inhalable gaseous drug containing argon (Ar), oxygen (O ₂ ) and nitrogen (N ₂ ) for use in a method of treatment, attenuation or resorption of cerebral damage following an ischemic cerebrovascular accident (CVA) in an individual subsequently undergoing mechanical thrombectomy, said method comprising:

(a) administration of the Ar/O ₂ /N ₂ gaseous drug by inhalation after said ischemic stroke (iCVA),

(b) followed by mechanical thrombectomy with mechanical removal of at least part of the blood clot resulting from the iCVA,

and wherein administering the gaseous drug by inhalation:

i) is started as soon as possible after a diagnosis of iCVA, and

ii) is maintained throughout the entire thrombectomy, and

ii) it is preferentially continued after the mechanical thrombectomy, ie after reperfusion.

The Ar/O ₂ /N ₂ gaseous drug is therefore in a form suitable for administration by inhalation in an individual subsequently having to undergo a mechanical thrombectomy with a view to eliminating all or part of the blood clot linked to the AVCi, the administration gaseous drug starting after the ischemic cerebrovascular accident (iCVA), in particular after diagnosis, ie confirmation, of the iCVA, and before the start of the mechanical thrombectomy and continues during the mechanical thrombectomy and preferably also after the mechanical thrombectomy , i.e. after reperfusion.

According to the embodiment considered, the gaseous drug Ar/O ₂ /N ₂ of the invention may comprise one or more of the following characteristics:

• it contains an effective volumetric proportion of argon.
• argon is the active ingredient of the drug.
• it is made up of argon, oxygen and nitrogen.
• the volume proportion of argon is between 40 and 70% (vol.%).
• the volume proportion of argon is between 50 and 70%.
• the volume proportion of argon is between 55 and 65%.
• the volume proportion of argon is between 58 and 63%.
• the proportion by volume of argon is equal to approximately 60%.
• the volume proportion of oxygen is between 21 and 40% (vol.%).
• the volume proportion of oxygen is between 25 and 35%.
• the volume proportion of oxygen is between 25 and 31%.
• the volume proportion of nitrogen is between 9 and 29% (vol.%).
• the volume proportion of nitrogen is between 9 and 25%.
• the volume proportion of nitrogen is between 9 and 15%.
• it consists of 58 to 62% argon, 9 to 15% nitrogen and oxygen for the rest.
• it consists of 60% argon, 9 to 15% nitrogen and 25 to 31% oxygen.
• it does not contain xenon.
• it is in a form suitable for administration by inhalation before, during and/or after the mechanical thrombectomy.
• it is in a form suitable for inhaled administration via the nasal, buccal or pharyngeal route, including naso-buccal.
• it is in a form suitable for administration by inhalation as soon as possible after a diagnosis of AVCi, that is to say in the minute or minutes following the diagnosis of AVCi so as to avoid aggravation of the AVCi. The faster the administration, i.e. without delay, the more the deleterious effects of the iCVA on the patient can be reduced, i.e. limited or minimized.
• it is in a form suitable for administration by inhalation after the mechanical thrombectomy, that is to say that it is maintained for several minutes or tens of minutes after the reperfusion subsequent to the thrombectomy, preferably for at least 10 minutes , more preferably for at least 15 to 20 minutes, advantageously for at least 30 minutes, preferably at least 45 minutes, and even up to at least 60 minutes, or even longer, after reperfusion.
• the individual (i.e. the patient) is an adult, an adolescent or a child.
• the individual is an adult at least 40 years old, preferably at least 50 years old.
• it is combined with mechanical thrombectomy with or without drug thrombolysis, i.e. possibly with the administration of a drug to thin the blood and break up at least part of the clot.
• the proportion of argon is chosen to act effectively on the brain cells in the penumbra zone weakened by the AVCi.
• the proportion of argon is chosen to improve the neuronal plasticity of brain cells in the penumbra zone.
• the cerebral lesions are of the inflammation, blood-brain barrier, cell apoptosis, tissue necrosis, edema or other types.
• mechanical thrombectomy involves mechanical extraction of the blood clot by means of a probe inserted into a blood vessel, in particular an artery.
• the method of treating, mitigating or resolving cerebral damage resulting from stroke includes sedating the patient at least during the mechanical thrombectomy, i.e. the mechanical thrombectomy is performed on a patient under general anesthesia or local anesthesia, preferably combined with conscious sedation.
• the method of treatment, attenuation or resorption of cerebral lesions consecutive to AVCi comprises sedation of the patient by administration of one or more sedative, analgesic or anesthetic products, for example halothane, isoflurane, desflurane, sevoflurane, thiopental, propofol, fentanyl, midazolam, propofol, remifentanyl or other.
• the ternary Ar/O ₂ /N ₂ gaseous drug is packaged in a pressurized gas container, in particular a pressurized gas cylinder.
• the ternary gaseous drug Ar/O ₂ /N ₂ coming from the pressurized gas container is administered to the patient via inhalation via the nasal, buccal or pharyngeal route, ie tracheally, including naso-buccal, by means of a suitable respiratory interface , such as a mask, nasal cannulas or a tracheal tube for example.
• according to another embodiment, the gaseous drug Ar/O ₂ /N ₂ is obtained by mixing on site of use gases originating from different gaseous sources (such as bottles/receptacle or pipes/pipes/supply lines), for example an argon cylinder or an argon supply line, an oxygen cylinder or an oxygen supply line, and a nitrogen cylinder or a nitrogen supply line, or from an Ar/O ₂ premix (bottle or pipe) diluted with nitrogen (bottle or pipe), or even ambient air to which oxygen and/or argon have been added, until the desired proportions are obtained, for example at means of a gas mixer.
• the Ar/O ₂ /N ₂ drug gas from the pressurized gas container is administered to the patient by means of a medical gas administration device, i.e. either a valve adapted to the spontaneous breathing of the gaseous medicine, or an assisted ventilation device (or medical ventilator) supplying the patient with gaseous medicine, preferably via a suitable respiratory interface fluidically connected to the medical device for administering gas via a flexible pipe or the like.

The method of administering argon to an individual, i.e. a patient, having a CVA is for example the following:

1. a gaseous drug Ar/O ₂ /N ₂ (% by vol.) is inhaled by means of a breathing device adapted for nasal, oral or tracheal administration, for example a breathing mask or a tracheal tube, to a patient immediately after confirmation of the diagnosis of stroke by cerebral imaging, for example of the scanner (CT) or MRI type;
2. administration by inhalation of the Ar/O ₂ /N ₂ drug gas is continued throughout the preparation for a mechanical thrombectomy procedure, typically for about 15 to 45 minutes, and during the actual mechanical thrombectomy procedure, as described above; and
3. preferably, the administration by inhalation of the Ar/O ₂ /N ₂ gaseous drug is stopped after the mechanical thrombectomy procedure, that is to say after the removal of the clot by means of a probe, preferably several minutes after the thrombectomy, preferably at least 10 to 15 minutes after reperfusion, more preferably between 10 and 60 minutes after reperfusion, typically about 30 minutes after reperfusion.

Preferably, the mechanical thrombectomy procedure is accompanied by, i.e. is associated with, drug thrombolysis with administration of a drug agent to thin the blood and break up the clot.

Furthermore, the mechanical thrombectomy procedure is performed with general or local anesthesia (e.g. locoregional) or conscious sedation of the patient.

In general, when the Ar/O ₂ /N ₂ mixture is administered by inhalation to the patient undergoing a stroke, for example a breathing mask or a tracheal tube, the inhaled argon (ie content between 30 and 70%) allows to treat the weakened brain cells during post-stroke ischemia and therefore to reduce the extent and the final volume of the cerebral lesions of such a stroke, after reperfusion following a mechanical thrombectomy, that is to say administered before, but especially during and after the procedure for resolution of the stroke by mechanical thrombectomy, with or without thrombolysis, aimed at eliminating the blood clot which has formed and which has caused the stroke.

Argon (ie content between 30 and 70%) of the Ar/O ₂ /N ₂ mixture improves neuronal plasticity in the penumbra zone, i.e. the zone of cells weakened by ischemia cerebral, when the AVCi event is resolved within a few hours by mechanical thrombectomy (with or without thrombolysis). Argon treats the neurological deficit and also allows accelerated recovery, therefore a faster return to normal life.

It is preferable to start the administration by inhalation of the Ar/O ₂ /N ₂ mixture containing an argon content between 30 and 70%, as soon as possible after the diagnosis and to maintain this administration throughout the procedure for resolving the problem. stroke, i.e. during mechanical thrombectomy, with or without thrombolysis, as well as for at least 30 minutes after reperfusion following removal of the blood clot.

Argon (ie content between 30 and 70%) is mixed with oxygen and nitrogen or co-administered with these compounds, as explained above, including obtained by mixing on the site of use at from different sources of the compounds of the Ar/O ₂ /N ₂ mixture.

Furthermore, limiting the quantity of oxygen in the Ar/O ₂ /N ₂ mixture which also contains 30 and 70% argon, by incorporating 9 and 42% nitrogen therein, makes it possible to avoid any overoxygenation of the patient. likely to be generated by an excess of oxygen in the mixture. Indeed, overoxygenation could lead to a risk of induction of oxidative phenomena and production of reactive “oxygenated” compounds or ROS (ie Reactive Oxygen Species) in the weakened areas of the brain, which could be deleterious at the time of reperfusion. However, care is taken to ensure that the quantity of oxygen is always at least 21% to avoid, conversely, hypoxia of the patient.

The advantage of nitrogen is that it can be substituted for oxygen (and/or dilute it) but without causing negative or undesirable effects on the patient, due to its inert nature and this, unlike other so-called “inert” gases such as helium or xenon which could modify or influence the characteristics of the mixture in a way that is not necessarily desired or desirable.

Advantageously, an Ar/O ₂ /N ₂ mixture containing approximately 60% argon, 9 to 15% nitrogen and 25 to 31% oxygen is used, which is the mixture considered to be the most effective, making it possible to maintain oxygenation compatible with the vital needs of the individual treated but without leading to overoxygenation of the patient, therefore by limiting or eliminating the risk of induction of the aforementioned oxidative phenomena and production of ROS, likely to be deleterious to the time of reperfusion.

Claims (10)

Inhalable gaseous drug containing argon, nitrogen, and oxygen gas for use in treating, mitigating, or reversing brain damage resulting from ischemic stroke (CVA) in an individual undergoing mechanical thrombectomy , the proportion by volume of argon being between 30 and 70%, the proportion by volume of oxygen being at least 21% and the proportion by volume of nitrogen being between 9 and 42%. Medicament according to Claim 1, characterized in that the volume proportion of argon is between 40 and 70%. Medicament according to one of the preceding claims, characterized in that the proportion by volume of argon is between 50 and 70%. Medicament according to one of the preceding claims, characterized in that the proportion by volume of argon is between 55 and 65%. Medicament according to Claim 1, characterized in that the proportion by volume of oxygen is between 21 and 40%. Medicament according to Claim 5, characterized in that the proportion by volume of oxygen is between 25 and 35%. Medicament according to Claim 1, characterized in that the proportion by volume of nitrogen is between 9 and 29%. Medicine according to Claim 7, characterized in that the volume proportion of nitrogen is between 9 and 15%. Medicament according to one of the preceding claims, characterized in that it consists of 58 to 62% argon, 9 to 15% nitrogen and the remainder oxygen. Medicament according to one of the preceding claims, characterized in that it consists of 60% argon, 9 to 15% nitrogen and 25 to 31% oxygen.