FR2816212A1 - Use of carbon monoxide to treat or prevent cardiovascular inflammation e.g. ischemia, reperfusion, stenosis, restenosis, and platelet aggregation - Google Patents

Abstract

The use of carbon monoxide or a carbon monoxide donor in medicines to treat or prevent inflammation in human or animal cardiovascular systems.

Description

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 The invention relates to a use of carbon monoxide (CO) or of a CO donor for manufacturing all or part of a medicament intended to treat or prevent an inflammatory and / or proliferative pathology of the cardiovascular system in humans. man or animal, in particular a pathology resulting from an ischemia / re-perfusion syndrome, a stenosis, a re-stenosis ..., in particular all or part of an inhalable gaseous medicament.

 It is known that arterial thrombosis is the consequence of an intravascular formation, in particular an atheroma plaque due for example to deposits of cholesterol on the internal walls of the vessels.

 However, arteriosclerotic deposits reduce the diameter of the arteries and therefore reduce the arterial circulation downstream of the thrombus.

 This reduction in tissue oxygenation leads to cell destruction responsible for infarction of muscle tissue, such as myocardial infarction, which can go as far as the death of the infarcted organ and jeopardize the vital prognosis.

 Several drug agents have been tried as antithrombotics, such as aspirin, prostaglandin E1, selective thromboxane A2 inhibitors, selective thrombin inhibitors, platelet GPllb / llia receptor blockers, tissue plasmogen activators, streptokinases , heparin ...

 However, the most widespread treatment remains angioplasty which is an interventional technique usually using a device with an inflatable balloon or, more recently, a laser beam or a scraping device.

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 Indeed, coronary angioplasty is a medical technique based on an internal "planing" of the vessel aimed at mechanically eliminating the arteriosclerosus.

les documents suivants : Genetic risk factors and restenosis after percutaneous coronary interventions, A. Kastrati et al., Deutsches Herzzentrum Muenchen, 25 février 2000 ; Endoprothèses coronaires à la phase aiguë de l'infarctus du myocarde : mise au point, P Le Corvoisir et al, STV n 3, vol. 11, mars 1999 ; Stents coronariens : expétience clinique et rapport coûts-efficacité, H. Z. Noorani, fév. 1997 ; Les maladies cardiovasculaires, Fondation pour la Recherche Médicale, J. B. Michel et al, Mars 1997. The phenomenon of restenosis is also described in particular in

the following documents: Genetic risk factors and restenosis after percutaneous coronary interventions, A. Kastrati et al., Deutsches Herzzentrum Muenchen, February 25, 2000; Coronary stents in the acute phase of myocardial infarction: update, P Le Corvoisir et al, STV n 3, vol. 11, March 1999; Coronary stents: clinical experience and cost-effectiveness, HZ Noorani, Feb. 1997 ; Cardiovascular diseases, Foundation for Medical Research, JB Michel et al, March 1997.

 Figures 1 and 2 appended hereto schematize the process (successive steps A to D in Fig. 1) of angioplasty treatment of an artery 2 having a lesion of stenosis type 1 by means of an intra-arterial catheter 6.

gonflé à haute pression, plaquant ainsi les dépôts ou sténose 1 obstruant la lumière du vaisseau 2 contre la paroi artérielle. During the intervention, the downstream end of the intra-arterial catheter 6 provided with a balloon 5 is introduced into the artery 2 and the balloon 5 is

inflated at high pressure, thereby pressing the deposits or stenosis 1 obstructing the lumen of the vessel 2 against the arterial wall.

 If this method makes it possible to restore the arterial circulation more often thanks to a "repair" 4 of the injured artery which it allows to obtain, it also inevitably causes damage in the arterial wall caused by the balloon 5 which can lead to restenosis 3, in 30 to 50% of cases within 6 months of the operation.

 Indeed, angioplasty creates damage to the arterial wall, such as lacerations or cracks caused by the balloon 5, which can be responsible for an proliferation of smooth muscle cells resulting from hyperplasia of the inner layer of the vessel wall or intima or restenosis 3.

 This proliferation could be due to growth factors

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relargués par les plaquettes lors de leur adhésion sur le site de la lésion de la paroi.

released by the platelets when they adhere to the site of the wall lesion.

However, a major complication that may result is a rupture of the wall of the coronary artery, which then requires the urgent implementation of a bypass surgery.

Another mechanism at the origin of restenosis would involve a remodeling of the media of the vessel inducing a chronic vasoconstriction of the artery leading to restenosis.

 In order to reduce this rate of restenosis, techniques using the placement of mechanical devices such as "stents" have been proposed in order to keep the artery open.

 However, the phenomenon of restenosis remains the most frequent complication of angioplasty with placement of a "stent", namely approximately 20% of patients.

de NO en tant que médicament pouvant traiter ou prévenir une thrombose. En effet, il a été montré expérimentalement que la molécule de NO avait une action inhibitrice de la prolifération des cellules de muscle lisse en culture. Another treatment method is proposed by document WO-A-96/25184 which describes the use of nitric oxide (NO) or of a donor

NO as a medicine that can treat or prevent thrombosis. Indeed, it has been shown experimentally that the NO molecule has an inhibitory action on the proliferation of smooth muscle cells in culture.

 Furthermore, document WO-A-97/37644 describes, for its part, the use of nitrogen monoxide (NO) or carbon monoxide (CO) in the treatment of hemoglobinopathies.

mammifère ; le CO endogène ayant vraisemblablement une activité de modulateur de l'hême oxydase. More recently, endogenous carbon monoxide (CO) synthesized by body cells has been proposed as the main route of activity for heme oxidase, the basic molecule of the inflammatory system in humans.

mammal; endogenous CO probably having a modulating activity of heme oxidase.

However, to this day, there still exists the need for an effective drug to combat the phenomena of ischemia / reperfusion, stenosis or vascular restenosis, and against the problems which are linked to

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 these phenomena, in particular that of cell proliferation and platelet aggregation.

 On this basis, the problem which arises is to propose a therapeutic composition which is really effective in combating inflammatory and / or proliferative pathologies of the cardiovascular system resulting from ischemia / re-perfusion, stenosis or re-stenosis, especially easily administered by inhalation.

 In other words, the aim of the present invention is then to solve the above problem, that is to say to propose a therapeutic product making it possible to effectively treat inflammatory and proliferative pathologies of the cardiovascular system, in particular an inflammatory pathology resulting re-perfusion ischemia, stenosis or re-stenosis, which therapeutic product is also easy to produce on an industrial level.

 The invention therefore relates to the use of carbon monoxide (CO) or of a carbon monoxide (CO) donor agent for manufacturing a medicament or part of a medicament intended for treating or preventing inflammation of the cardiovascular system in man or animal.

 According to another aspect, the invention also relates to the use of carbon monoxide (CO) or of a carbon monoxide (CO) donor agent for manufacturing a medicament or part of a medicament intended to treat or prevent a ischemia syndrome 1 re-perfusion, stenosis or restenosis of the cardiovascular system in humans or animals.

 According to yet another aspect, the invention relates to the use of carbon monoxide (CO) or of a carbon monoxide (CO) donor agent to manufacture a medicament or part of a medicament intended to treat or prevent a platelet aggregation of the cardiovascular system in humans or animals.

 In the context of the invention, by "donor agent of monoxide of

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ou à l'animal, par exemple au niveau ou dans l'organe cible à traiter. Il va de soi que le CO endogène, c'est-à-dire le CO synthétisé directement par le corps de l'homme ou de l'animal, est exclus de la présente invention. carbon (CO) "means one or more molecules, or one or more products or substances capable of fixing and / or transporting one or more CO molecules and subsequently of releasing and / or releasing said CO molecule (s), particular after its administration to humans

or to the animal, for example at the level or in the target organ to be treated. It goes without saying that endogenous CO, that is to say CO synthesized directly by the body of man or animal, is excluded from the present invention.

 Furthermore, the term "manufacture" is considered in its most generic sense and is considered to be completely equivalent to analogous terms such as "prepare".

 Depending on the case, the use of the invention may include one or more of the following characteristics: - which the inflammation or platelet aggregation of the cardiovascular system results from ischemia re-perfusion, stenosis or 're-stenosis.

 - carbon monoxide (CO) or the carbon monoxide (CO) donor agent is associated with at least one active product with anti-inflammatory action to manufacture a medicament or part of a medicament intended to treat or prevent inflammation of the cardiovascular system.

 - carbon monoxide (CO) or the carbon monoxide (CO) donor is in gaseous or aerosol form.

carbone (CO) est associé à au moins un gaz choisi parmi le monoxyde d'azote (NO), le dioxyde de carbone (CO2), l'hélium, l'oxygène, l'azote et leurs mélanges, préférentiellement le monoxyde d'azote (NO). - carbon monoxide (CO) or the donor of monoxide of

carbon (CO) is associated with at least one gas chosen from nitrogen monoxide (NO), carbon dioxide (CO2), helium, oxygen, nitrogen and their mixtures, preferably carbon monoxide nitrogen (NO).

 - the active product with anti-inflammatory action is chosen from steroidal anti-inflammatory drugs (AIS), in particular corticosteroids, mineralosteroids and their mixtures.

 - the active product with anti-inflammatory action is chosen from non-steroidal anti-inflammatory drugs (NSAIDs).

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the active product is chosen from indoliques and derivatives, arylcarboxylics, oxicam derivatives, salicylates and their mixtures.

thrombotique, tel PGE1, les inhibiteurs du TXA2, la streptokinase, 1'urokinase, l'aleplase, l'héparine, les antagonistes des récepteurs GP)) b/) !) a, tel le REOPRO inj., les anti-aggrégants plaquettaires, tel que aspirine, ticlopidine... - carbon monoxide (CO) or the donor of carbon monoxide (CO) is associated with at least one active product with anti-

thrombotic, such as PGE1, TXA2 inhibitors, streptokinase, urokinase, aleplase, heparin, GP receptor antagonists)) b /)!) a, such as REOPRO inj., antiplatelet agents , such as aspirin, ticlopidine ...

 the medicament or the part of medicament is in inhalable form, preferably in gaseous or aerosol form.

 - carbon monoxide (CO) or the carbon monoxide donor agent is used in the composition of a drug which can be administered by inhaled, enteral, parenteral, transcutaneous or transdermal route.

entre 1 ppb et 1000 ppm, préférentiellement inférieure à 600 ppm. - the drug contains a therapeutically effective amount of carbon monoxide (CO), preferably the amount of CO is included

between 1 ppb and 1000 ppm, preferably less than 600 ppm.

- the medicine contains less than 500 ppm carbon monoxide (CO).

In summary, the present invention is based on the demonstration by the inventors that carbon monoxide (CO), usually presented as a toxic gas, can be used for therapeutic purposes and, more specifically, that CO can have a therapeutic activity due to its anti-proliferative and anti-aggregating platelet properties.

 From there, carbon monoxide (CO) is likely to be used to combat various disorders or pathologies in humans, in particular any inflammatory and / or proliferative pathology resulting from ischemia reperfusion, stenosis or d 're-stenosis.

 Although the mode of action of CO is not fully known to date, it is likely that it is not necessarily linked to the CGMP-cyclic pathway as demonstrated with NO.

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 CO activity is more likely linked to another pathway involving an activated mitogenic protein kinase (MAP).

 This anti-inflammatory activity by a route other than CGMPcyclic strengthens the association of the two gaseous molecules NO and CO. It is logical to think that the anti-inflammatory and anti-protiferative action of the NO / CO mixture is more important than that of the two molecules taken in isolation; in other words, that these two molecules act in synergy.

 We can therefore say that the use of CO, possibly coupled with NO, therefore opens up new therapeutic possibilities in the field of inflammation and cell proliferation of the vascular walls.

 CO can be administered by inhalation, i.e. CO is administered to the patient via their respiratory tract using a CO delivery device, such as a ventilator connect a source of CO so as to administer the CO to the patient via a respiratory mask, respiratory glasses or a cannula.

 The administration of CO gas can be done either continuously or in a pulsed manner, that is to say during all or part of each inspiratory phase of the patient. In the second case, the detection of the beginning and / or the end of each inspiratory and / or expiratory phase is conventionally done by means of a device adapted for this purpose.

 When CO is delivered in gaseous form by the inhaled route to a patient, care is taken that the respiratory gas administered to the patient contains, in addition to the CO or the CO donor, oxygen in nonhypoxic quantity, it is that is to say a proportion sufficient to ensure correct ventilation of the patient, such as air or a gaseous mixture containing on the order of 19 to 23% of oxygen, the remainder being one or more inert gases, such as nitrogen.

 As part of the implementation of a treatment method

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thérapeutique selon l'invention, l'administration du CO ou du donneur de CO se fait, par exemple, par le biais d'un dispositif de type stent.

therapeutic according to the invention, the administration of the CO or of the CO donor is done, for example, by means of a stent-type device.

Claims (22)

 1, Use of carbon monoxide (CO) or a carbon monoxide (CO) donor agent to manufacture a medicament or part of a medicament intended to treat or prevent inflammation of the cardiovascular system in man or woman 'animal.

claims  2. Use of carbon monoxide (CO) or a carbon monoxide (CO) donor agent to make a medicine or part of a medicine to treat or prevent ischemia / reperfusion syndrome, stenosis or restenosis of the cardiovascular system in humans or animals.  3. Use of carbon monoxide (CO) or a carbon monoxide (CO) donor agent to manufacture a medicament or part of a medicament intended to treat or prevent platelet aggregation of the cardiovascular system in humans or the animal.  4. Use according to one of claims 1 or 3, wherein the inflammation or platelet aggregation of the cardiovascular system results from ischemia re-perfusion, stenosis or re-stenosis.  5. Use according to one of claims 1 to 4, wherein the carbon monoxide (CO) or the carbon monoxide donor agent

 (CO) is associated with at least one active product with anti-inflammatory action to manufacture a medicament or part of a medicament intended to treat or prevent an inflammation of the cardiovascular system.  6. Use according to one of claims 1 to 5, wherein the <Desc / Clms Page number 10>  carbon monoxide (CO) or the carbon monoxide (CO) donor agent is associated with at least one gas chosen from nitrogen monoxide (NO), carbon dioxide (CO2), helium, oxygen, nitrogen and their mixtures, preferably NO.  7. Use according to one of claims 1 to 6, wherein the carbon monoxide (CO) or the donor of carbon monoxide (CO) is in gaseous or aerosol form.  8. Use according to one of claims 1 to 7, in which the medicament or the part of said medicament additionally contains at least one additional gas chosen from xenon, hydrogen, nitrous oxide (N2O), carbon or fluoro-carbon hydrocarbons, and mixtures of several of these gases.  9. Use according to claim 5, in which the active product with anti-inflammatory action is chosen from steroidal anti-inflammatory drugs (AIS), in particular corticosteroids, mineralosteroids and their mixtures.

10. Use according to claim 5, in which the active product with anti-inflammatory action is chosen from non-steroidal steroidal anti-inflammatory drugs (NSAIDs).  11. Use according to one of claims 5 or 10, in which the active product is chosen from indolics and derivatives, arylcarboxylics, oxicam derivatives, salicylates and their mixtures.  12. Use according to one of claims 1 to 11, in which the medicament or the medicament part is in inhalable form, <Desc / Clms Page number 11>  preferably in gaseous or aerosol form.  13. Use according to one of claims 1 to 12, in which carbon monoxide (CO) or the carbon monoxide donor agent is included in the composition of a drug which can be administered by inhaled, enteral, parenteral, transcutaneous or transdermal.  14. Use according to one of claims 1 to 13, wherein the medicament contains a therapeutically effective amount of monoxide

 carbon (CO), preferably the amount of CO is between 1 ppb and 1000 ppm, preferably less than 600 ppm. 15. Use according to claim 5, in which the carbon monoxide (CO) or the carbon monoxide donor (CO) is associated with at least one active product with anti-thrombotic action, at least one TXA2 inhibitor, streptokinase , Urokinase, aleplase, heparin, at least one GPllb / IIIa receptor antagonist, at least one platelet aggregation inhibitor or ticlopidine.  16. Carbon monoxide (CO) or carbon monoxide (CO) donor in gaseous or aerosol form as a medicine or part of a medicine intended to treat or prevent inflammation of the cardiovascular system, syndrome of ischemia / re-perfusion, stenosis, restenosis and / or platelet aggregation of the cardiovascular system in humans or animals.  17. Mixture in gaseous form or in aerosol form containing carbon monoxide (CO) or a carbon monoxide (CO) donor associated with nitrogen monoxide (NO) or a nitrogen monoxide donor ( NO) as a medicine or part of a medicine intended for <Desc / Clms Page number 12>  treat or prevent inflammation of the cardiovascular system, ischemia / re-perfusion syndrome, stenosis, restenosis and / or platelet aggregation of the cardiovascular system in humans or animals.  18. Mixture in gaseous or aerosol form of carbon monoxide (CO) or of a carbon monoxide (CO) donor

 associated with nitric oxide (NO) or a donor of nitric oxide (NO) and at least one active product as a drug or part of a drug intended to treat or prevent inflammation of the cardiovascular system, a ischemia / re-perfusion syndrome, stenosis, restenosis and / or platelet aggregation of the cardiovascular system in humans or animals.  19. A mixture according to claim 18, in which the active product is chosen from compounds with anti-thrombotic action, TXA2 inhibitors, streptokinase, urokinase, aleplase, heparin, antagonists

 GPllb / llla receptors, platelet aggregation inhibitors or ticlopidine.  20. A mixture according to claim 18, containing (by volume) from 100 ppb to 500 ppm of NO, less than 10% of CO2, from 20 to 85% of helium, from 18 to 50% of oxygen and from 10 to 99.999% nitrogen.  21. Gas mixture or aerosol mixture of carbon monoxide (CO) or of a carbon monoxide (CO) donor, possibly associated with nitrogen monoxide (NO) or a nitrogen monoxide donor (NO), and containing at least one gas chosen from carbon dioxide (CO2), helium, oxygen, nitrogen and their mixtures and optionally at least one additional gas chosen from xenon, hydrogen, nitrous oxide (N2O), carbonaceous hydrocarbons or <Desc / Clms Page number 13>  fluorocarbons, and mixtures thereof.

 22. Container of pressurized fluid, in particular a gas bottle, containing a gas or a gaseous mixture according to one of claims 16 to 21.