WO1998001142A1 - Nitric oxide inhalation for the prophylaxis and treatment of inflammatory response - Google Patents
Nitric oxide inhalation for the prophylaxis and treatment of inflammatory responseInfo
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- WO1998001142A1 WO1998001142A1 PCT/CA1997/000428 CA9700428W WO9801142A1 WO 1998001142 A1 WO1998001142 A1 WO 1998001142A1 CA 9700428 W CA9700428 W CA 9700428W WO 9801142 A1 WO9801142 A1 WO 9801142A1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
Definitions
- the present invention relates to the use of nitric oxide for the manufacture of a medicament for inhalation intended for humans or animals.
- a drug to be inhaled can be used for the purposes of prevention and / or treatment of immune reactions of the inflammatory type caused by temporary extra-corporeal blood circulation, in particular during a cardiac surgery operation.
- Nitric oxide is produced naturally in humans or animals by an enzyme, NO-synthase, which is expressed constitutively in endothelial cells, platelets, and the central and peripheral nervous systems. Another form of calcium-independent NO-synthase can be induced by different stimuli, including liposaccharides, in many cells such as macrophages, lymphocytes, myocardial cells, endothelial and smooth muscle cells. Nitric oxide is also produced in large quantities in the respiratory tract, particularly in the paranasal sinuses. Each time you breathe in, the nitrogen monoxide produced is self-inhaled.
- Nitric oxide is therefore an important biological messenger in humans and animals.
- NO also plays a decisive role in the local control of hemodynamics. Indeed, the release of NO by endothelial cells has been demonstrated in the event of variations in blood flow. Nitrogen monoxide appears in particular as a major component of the physiological adaptation of the vascular diameter to blood perfusion; thus, at the coronary level, reactive hyperaemia is markedly attenuated in the absence of NO. Conversely, a chronic increase in blood flow produced by an arteriovenous fistula increases dependent relaxations of the endothelium.
- the NO produced at the level of the vascular wall and in the surrounding tissues therefore participates in the precise regulation of the vascular tone by adaptation of the blood flow.
- NO has the property of maintaining a low pressure in the pulmonary circulation, which results in a local vasodilator effect, has suggested its use in the context of therapeutic treatments in patients suffering from respiratory diseases , especially in the treatment of acute pulmonary hypertension.
- Patent application WO 92/10228 and other publications describe the use of inhaled NO for the treatment of pulmonary vasoconstriction and asthma.
- This document teaches the use of inhaled NO for therapeutic or diagnostic purposes in the case of respiratory diseases localized in the patient's lungs. It is explained in particular that since NO which enters the bloodstream would be rapidly inactivated by combination with hemoglobin, the effects of inhaled NO would be limited to blood vessels near the site of entry of NO into the circulation , i.e. to the pulmonary microvessels.
- US patent 5,427,797 relates has, meanwhile, use of inhaled NO to inhibit blood coagulation and platelet aggregation that occur in patients with acute respiratory diseases such as Acute Respiratory Distress Syndrome.
- inhaled NO can also be used to prevent or treat inflammations resulting from extra-bodily blood circulation.
- inhaled NO can also be used to prevent or treat inflammations resulting from extra-bodily blood circulation.
- patients suffer from an acute nitric oxide deficiency and thus become more susceptible to inflammatory reactions arising from extra-bodily blood circulation.
- the extra-corporeal circulation leads to the activation of the inflammatory process, in particular the production of cytotoxins and adhesion molecules, and an activation of circulating cells, in particular leukocytes, which migrate towards the vascular endothelium.
- the lungs are not spared since the inflammatory state induces there high arterial pressures due to the obstruction of the microcirculation by aggregates of circulating cells, in particular leukocytes, and a vasoconstriction phenomenon, and this can result in pulmonary edema.
- the present invention therefore relates to the use of nitric oxide (NO) as a medicament or component of an inhaled medicament intended for preventing or combating inflammatory reactions consecutive to an extra-corporeal blood circulation in man or woman. 'animal.
- NO nitric oxide
- the inventor of the present invention has demonstrated the extrapulmonary effects resulting from an inhalation treatment of nitric oxide following an extracorporeal blood circulation.
- the inventor has also demonstrated other systemic effects of nitric oxide, a relaxing effect in the left ventricle of the heart muscle.
- Said drug to be inhaled is administered to humans or animals, preferably at least during part of the operative preparation phase.
- the administration of inhaled NO to the patient (man or animal) from the operative preparation phase that is to say the time phase preceding the first incision and during which the patient is anesthetized and intubated, makes it possible to considerably reduce, or even avoid, any inflammation during the actual operating phase during which the extra-corporeal blood circulation takes place as well as during the postoperative phase.
- said drug to be inhaled is administered by oral or nasal intubation at an effective concentration.
- NO delivery devices that can be used in the context of the present invention are of conventional type; as non-limiting example may be cited the device described in the patent EP 589 751. N has however 0 during the period of extracorporeal circulation, said drug for inhalation may also be administered to the same device blood circulation comprising a membrane oxygenator or operating on any other equivalent principle.
- said medicament to be inhaled is a mixture of gases comprising nitrogen monoxide.
- the drug to be inhaled can also be a vaporization of a NO-containing or otherwise NO-donating substance.
- said gas mixture comprises nitrogen monoxide and at least one compound chosen from the group formed by N 2 , He, Ar, CO 2 , Xe, Kr, O 2 and their mixtures.
- any inert gas, non-oxidizing and without biological activity is suitable.
- the concentration of nitric oxide in said drug to be inhaled is between 0.5 ppm and 80 ppm, preferably between 1 and 40 ppm, and more preferably, between 3 ppm and 10 ppm, advantageously of the order of 5 ppm.
- Patient monitoring is carried out according to the usual procedures, but additional examinations may nevertheless be included, in particular:
- Group 1 is the control group.
- Group 2 is the hypoxia control group in which pigs inhale a hypoxic gas mixture (15% Fi0 2 ) causing pulmonary vasoconstriction and triggering inflammatory reactions.
- Group 3 is the group receiving NO inhaled at a concentration of 40 ppm.
- Group 4 is the group inhaling a hypoxic gas mixture containing 40 ppm NO.
- catheters were placed in the ureters, the aorta and the renal vein and two markers were injected continuously, they are inuiine and para-amino-hippu ⁇ que acid
- the measurement of the clearance of the two markers makes it possible to calculate the blood flow and the glomerular filtration rate.
- urine flow is also measured.
- the pigs receiving inhaled NO have a urinary flow rate, a glomerular filtration rate and a renal blood flow rate much higher than the control control pigs.
- hypoxia-induced vasoconstriction and inflammation reactions cause a marked decrease in renal blood flow.
- This effect of hypoperfusion of the kidney is at least partially offset by the inhalation of NO, which causes an increase in renal blood flow, glomerular filtration rate and urine flow.
- This study therefore confirms the effect of inhaled NO, which makes it possible to oppose vasoconstrictive and inflammatory systemic reactions, in particular by reducing the adhesion of circulating cells. This results in a beneficial effect on the so-called fragile organs, in particular on the renal, hepatic, cardiac, intestinal and neurological functions of the patient.
- the experiment was carried out in four stages: (i) basic physiological measurements, (ii) phase of pulmonary and systemic hypertension induced by an intravenous infusion of phenylephrine (iii) treatment with nitrogen monoxide or nitroglycerine, (iv ) recovery phase by discontinuation of all treatments.
- phase i In order to make the table easier to read, the measurement values for phase i have been deliberately set to 1; those given for phases ii, iii, and iv correspond to the correlation factors.
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Abstract
Description
MONOXYDE D'AZOTE INHALÉ POUR LA PRÉVENTION ET LE TRAITEMENT DES RÉACTIONS INFLAMMATOIRES INHALED NITROGEN MONOXIDE FOR THE PREVENTION AND TREATMENT OF INFLAMMATORY REACTIONS
La présente invention concerne l'utilisation de monoxyde d'azote pour la fabrication d'un médicament à inhaler destiné à l'homme ou à l'animal. Un tel médicament à inhaler est utilisable à des fins de prévention et/ou de traitement des réactions immunitaires de type inflammatoire provoquées par une circulation sanguine extra-corporelle temporaire, notamment lors d'une opération de chirurgie cardiaque.The present invention relates to the use of nitric oxide for the manufacture of a medicament for inhalation intended for humans or animals. Such a drug to be inhaled can be used for the purposes of prevention and / or treatment of immune reactions of the inflammatory type caused by temporary extra-corporeal blood circulation, in particular during a cardiac surgery operation.
Le monoxyde d'azote est produit naturellement chez l'homme ou l'animal par une enzyme, la NO-synthase, laquelle est exprimée de façon constitutive dans les cellules endothéliales, dans les plaquettes et dans le système nerveux central et périphérique. Une autre forme de NO-synthase calcium-indépendante peut être induite par différents stimuli, notamment les liposaccharides, dans de nombreuses cellules telles que les macrophages, les lymphocytes, les cellules myocardiques, les cellules endothéliales et musculaires lisses. Le monoxyde d'azote est aussi produit en quantité importante dans les voies respiratoires, particulièrement dans les sinus paranasaux. À chaque inspiration, le monoxyde d'azote ainsi produit est auto- inhalé.Nitric oxide is produced naturally in humans or animals by an enzyme, NO-synthase, which is expressed constitutively in endothelial cells, platelets, and the central and peripheral nervous systems. Another form of calcium-independent NO-synthase can be induced by different stimuli, including liposaccharides, in many cells such as macrophages, lymphocytes, myocardial cells, endothelial and smooth muscle cells. Nitric oxide is also produced in large quantities in the respiratory tract, particularly in the paranasal sinuses. Each time you breathe in, the nitrogen monoxide produced is self-inhaled.
Le monoxyde d'azote est donc un messager biologique important chez l'homme et l'animal.Nitric oxide is therefore an important biological messenger in humans and animals.
Parallèlement, le NO joue également un rôle déterminant dans le contrôle local de l'hémodynamique. En effet, la libération de NO par les cellules endothéliales a été mise en évidence en cas de variations du débit sanguin. Le monoxyde d'azote apparaît notamment comme une composante majeure de l'adaptation physiologique du diamètre vasculaire à la perfusion sanguine; ainsi, au niveau coronaire, l'hypérémie réactive est atténuée de façon notoire en l'absence de NO. Inversement, une augmentation chronique du débit sanguin produite par une fistule artérioveineuse augmente les relaxations dépendantes de l'endothélium.At the same time, NO also plays a decisive role in the local control of hemodynamics. Indeed, the release of NO by endothelial cells has been demonstrated in the event of variations in blood flow. Nitrogen monoxide appears in particular as a major component of the physiological adaptation of the vascular diameter to blood perfusion; thus, at the coronary level, reactive hyperaemia is markedly attenuated in the absence of NO. Conversely, a chronic increase in blood flow produced by an arteriovenous fistula increases dependent relaxations of the endothelium.
Le NO produit au niveau de la paroi vasculaire et dans les tissus avoisinants participe donc la régulation précise du tonus vasculaire par adaptation du débit sanguin.The NO produced at the level of the vascular wall and in the surrounding tissues therefore participates in the precise regulation of the vascular tone by adaptation of the blood flow.
En outre, le contrôle par le NO de la perméabilité veinulaire post-capillaire a également été mis en évidence.In addition, the NO control of post-capillary venous permeability was also highlighted.
Au vu des propriétés physiologiques du NO, son utilisation thérapeutique s'est avérée particulièrement intéressante.In view of the physiological properties of NO, its therapeutic use has proved to be particularly advantageous.
En particulier, le fait que le NO ait la propriété de maintenir une basse pression au niveau de la circulation pulmonaire, d'où il résulte un effet vasodilatateur local, a suggéré son utilisation dans le cadre de traitements thérapeutiques chez des patients atteints de maladies respiratoires, notamment dans le traitement de l'hypertension artérielle pulmonaire aiguë.In particular, the fact that NO has the property of maintaining a low pressure in the pulmonary circulation, which results in a local vasodilator effect, has suggested its use in the context of therapeutic treatments in patients suffering from respiratory diseases , especially in the treatment of acute pulmonary hypertension.
Ainsi, l'article de C.D.R. Borland et T.W. Higenbottam, paru sous la référence Eur. Respir. J., 1989, 2, 56-63 et le titre "A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide", montre, d'une part, l'influence d'une administration par inhalation de 40 ppm de NO sur l'augmentation de la concentration en oxygène alvéolaire et, d'autre part, que le NO inhalé réagit beaucoup plus vite avec l'hémoglobine que le CO inhalé.Thus, the article by CDR Borland and TW Higenbottam, published under the reference Eur. Breathe. J., 1989, 2, 56-63 and the title "A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide ", shows, on the one hand, the influence of an administration by inhalation of 40 ppm of NO on the increase in the concentration of alveolar oxygen and, on the other hand, that the inhaled NO reacts much faster with hemoglobin as CO inhaled.
La demande de brevet WO 92/10228 et d'autres publications décrivent l'utilisation du NO inhalé pour le traitement de la vasoconstriction pulmonaire et de l'asthme. Ce document enseigne l'utilisation du NO inhalé à des fins thérapeutiques ou diagnostiques dans le cas de maladies respiratoires localisées au niveau des poumons du patient. Il y est notamment expliqué qu'étant donné que le NO qui pénètre dans le circuit sanguin serait rapidement inactivé par combinaison à l'hémoglobine, les effets du NO inhalé seraient limités aux vaisseaux sanguins à proximité du site d'entrée du NO dans la circulation, c'est-à-dire aux microvaisseaux pulmonaires.Patent application WO 92/10228 and other publications describe the use of inhaled NO for the treatment of pulmonary vasoconstriction and asthma. This document teaches the use of inhaled NO for therapeutic or diagnostic purposes in the case of respiratory diseases localized in the patient's lungs. It is explained in particular that since NO which enters the bloodstream would be rapidly inactivated by combination with hemoglobin, the effects of inhaled NO would be limited to blood vessels near the site of entry of NO into the circulation , i.e. to the pulmonary microvessels.
Le brevet US Na 5,427,797 a trait, quant à lui, à l'utilisation du NO inhalé pour inhiber la coagulation et l'agrégation plaquettaire sanguine qui apparaissent chez des patients atteints de maladies respiratoires aiguës, tel le Syndrome de Détresse Respiratoire Aiguë.US patent 5,427,797 relates has, meanwhile, use of inhaled NO to inhibit blood coagulation and platelet aggregation that occur in patients with acute respiratory diseases such as Acute Respiratory Distress Syndrome.
En résumé, les publications existantes sont principalement axées vers une utilisation du NO inhalé pour le traitement ou la prophylaxie de l'hypertension pulmonaire.In summary, the existing publications are mainly focused on the use of inhaled NO for the treatment or prophylaxis of pulmonary hypertension.
L'inventeur de la présente invention a pour la première fois démontré que, de façon surprenante, le NO inhalé peut également être utilisé pour prévenir ou traiter les inflammations consécutives à une circulation sanguine extra-corporelle. Lors de certaines interventions chirurgicales, il est nécessaire de dévier la circulation sanguine du patient et de mettre en place une circulation sanguine extra-corporelle provisoire. C'est notamment le cas en chirurgie cardiaque, lorsqu'il est nécessaire d'effectuer un remplacement de valve, une correction de malformation congénitale ou un pontage coronarien. De plus, il est nécessaire d'intuber le patient de manière à ventiler mécaniquement. L'intubation signifie donc un arrêt de l'apport de monoxyde d'azote produit au niveau des voies respiratoires et particulièrement dans les sinus paranasaux. Par conséquent, les patients souffrent d'une déficience aiguë en monoxyde d'azote et deviennent ainsi plus susceptibles aux réactions inflammatoires découlant d'une circulation sanguine extra-corporelle.The inventor of the present invention has for the first time demonstrated that, surprisingly, inhaled NO can also be used to prevent or treat inflammations resulting from extra-bodily blood circulation. During certain surgical procedures, it is necessary to bypass the patient's blood circulation and to set up a temporary extra-corporeal blood circulation. This is particularly the case in cardiac surgery, when it is necessary to perform a valve replacement, a correction of a congenital malformation or bypass surgery. In addition, it is necessary to intubate the patient so as to ventilate mechanically. Intubation therefore means a cessation of the supply of nitric oxide produced in the respiratory tract and particularly in the paranasal sinuses. As a result, patients suffer from an acute nitric oxide deficiency and thus become more susceptible to inflammatory reactions arising from extra-bodily blood circulation.
Durant la chirurgie cardiaque le débit sanguin du coeur est supprimé, celui des poumons est réduit au minimum et celui des autres organes peut être réduit.During heart surgery the blood flow to the heart is suppressed, that to the lungs is minimized and that to other organs can be reduced.
La circulation extra-corporelle entraîne l'activation du processus inflammatoire, en particulier la production de cytotoxines et de molécules d'adhésion, et une activation des cellules circulantes, notamment des leucocytes, lesquels migrent vers l'endothélium vasculaire et s'y fixent. Il en résulte des réactions inflammatoires importantes, néfastes et à effets délétères au sein des organes les plus sensibles à l'hypoperfusion sanguine, tels le cerveau, les reins, le foie, le coeur et l'intestin.The extra-corporeal circulation leads to the activation of the inflammatory process, in particular the production of cytotoxins and adhesion molecules, and an activation of circulating cells, in particular leukocytes, which migrate towards the vascular endothelium. This results in major inflammatory reactions, harmful and with deleterious effects in the organs most sensitive to blood hypoperfusion, such as the brain, kidneys, liver, heart and intestine.
Les poumons ne sont pas épargnés puisque l'état inflammatoire y induit des pressions artérielles élevées dues à l'obstruction de la microcirculation par des agrégats de cellules circulantes, en particulier leucocytaires, et un phénomène de vasoconstriction, et il peut en résulter un oedème pulmonaire.The lungs are not spared since the inflammatory state induces there high arterial pressures due to the obstruction of the microcirculation by aggregates of circulating cells, in particular leukocytes, and a vasoconstriction phenomenon, and this can result in pulmonary edema.
Il est donc primordial de prévenir ou de traiter très précocement ce problème inflammatoire afin que les troubles et les dégâts occasionnés par l'inflammation soient minimisés, voire éliminés, et par conséquent, ce traitement précoce permet de réduire les coûts hospitaliers de prise en charge du patient étant donné que sa rémission sera, a priori, plus rapideIt is therefore essential to prevent or treat this inflammatory problem very early so that the disorders and damage caused by inflammation are minimized or even eliminated, and consequently, this early treatment makes it possible to reduce the hospital costs of managing the patient since his remission will, a priori, be faster
Afin de résoudre ce problème inflammatoire dû à une circulation extra-corporelle, les inventeurs de la présente invention ont mis en évidence l'effet bénéfique d'un apport précoce en NO inhalé.In order to solve this inflammatory problem due to an extra-corporeal circulation, the inventors of the present invention have demonstrated the beneficial effect of an early supply of inhaled NO.
La présente invention concerne donc l'utilisation de monoxyde d'azote (NO) en tant que médicament ou composante de médicament à inhaler destiné à prévenir ou à lutter contre les réactions inflammatoires consécutives à une circulation sanguine extra-corporelle chez l'homme ou l'animal.The present invention therefore relates to the use of nitric oxide (NO) as a medicament or component of an inhaled medicament intended for preventing or combating inflammatory reactions consecutive to an extra-corporeal blood circulation in man or woman. 'animal.
De façon surprenante, l'inventeur de la présente invention a démontré les effets extrapulmonaires résultant d'un traitement par inhalation de monoxyde d'azote suite à une circulation sanguine extra-corporelle. Le mécanisme exact permettant au monoxyde d'azote de voyager dans les vaisseaux sanguin pour se rendre à des organes périphériques, tels foie, reins, cerveau, intestin, coeur, n'est pas complètement élucidé De plus, l'inventeur a aussi démontré d'autres effets systémiques du monoxyde d'azote, soit un effet relaxant au niveau du ventricule gauche du muscle cardiaque.Surprisingly, the inventor of the present invention has demonstrated the extrapulmonary effects resulting from an inhalation treatment of nitric oxide following an extracorporeal blood circulation. The exact mechanism by which nitric oxide travels through blood vessels to reach peripheral organs, such as the liver, kidneys, brain, intestine, heart, is not fully understood In addition, the inventor has also demonstrated other systemic effects of nitric oxide, a relaxing effect in the left ventricle of the heart muscle.
Ledit médicament à inhaler est administré à l'homme ou à l'animal, de préférence, au moins durant une partie de la phase de préparation opératoire. En effet, l'administration de NO inhalé au patient (homme ou animal) dès la phase de préparation opératoire, c'est-à-dire la phase de temps précédant la première incision et durant laquelle le patient est anesthésie et intubé, permet de réduire considérablement, voire même d'éviter toute inflammation durant la phase opératoire proprement dite durant laquelle la circulation sanguine extra-corporelle a lieu ainsi que durant la phase postopératoire.Said drug to be inhaled is administered to humans or animals, preferably at least during part of the operative preparation phase. In fact, the administration of inhaled NO to the patient (man or animal) from the operative preparation phase, that is to say the time phase preceding the first incision and during which the patient is anesthetized and intubated, makes it possible to considerably reduce, or even avoid, any inflammation during the actual operating phase during which the extra-corporeal blood circulation takes place as well as during the postoperative phase.
De préférence, ledit médicament à inhaler est administré par intubation orale ou nasale à une concentration efficace. Les dispositifs d'administration de NO pouvant être utilisés dans le cadre de la présente invention sont de type classique; à titre d'exemple non limitatif peut être cité le dispositif décrit dans le brevet EP Na 0 589 751. Cependant, lors de la période de circulation sanguine extra-corporelle, ledit médicament à inhaler pourra aussi être administré à même l'appareil de circulation sanguine comprenant un oxygénateur à membrane ou fonctionnant sur tout autre principe équivalent.Preferably, said drug to be inhaled is administered by oral or nasal intubation at an effective concentration. NO delivery devices that can be used in the context of the present invention are of conventional type; as non-limiting example may be cited the device described in the patent EP 589 751. N has however 0 during the period of extracorporeal circulation, said drug for inhalation may also be administered to the same device blood circulation comprising a membrane oxygenator or operating on any other equivalent principle.
De manière préférée, ledit médicament à inhaler est un mélange de gaz comprenant le monoxyde d'azote. Cependant, le médicament à inhaler peut aussi être une vaporisation d'une substance contenant du NO ou autrement donneuse de NO. Préférentiellement, ledit mélange de gaz comprend le monoxyde d'azote et au moins un composé choisi dans le groupe formé par N2, He, Ar, CO2, Xe, Kr, O2 et leurs mélanges. En fait, tout gaz inerte, non-oxydant et sans activité biologique convient.Preferably, said medicament to be inhaled is a mixture of gases comprising nitrogen monoxide. However, the drug to be inhaled can also be a vaporization of a NO-containing or otherwise NO-donating substance. Preferably, said gas mixture comprises nitrogen monoxide and at least one compound chosen from the group formed by N 2 , He, Ar, CO 2 , Xe, Kr, O 2 and their mixtures. In fact, any inert gas, non-oxidizing and without biological activity is suitable.
Avantageusement, la concentration de monoxyde d'azote dans ledit médicament à inhaler est comprise entre 0,5 ppm et 80 ppm, de préférence entre 1 et 40 ppm, et préférentiellement encore, entre 3 ppm et 10 ppm, avantageusement de l'ordre de 5 ppm.Advantageously, the concentration of nitric oxide in said drug to be inhaled is between 0.5 ppm and 80 ppm, preferably between 1 and 40 ppm, and more preferably, between 3 ppm and 10 ppm, advantageously of the order of 5 ppm.
Le suivi du patient est effectué selon les procédures habituelles, mais des examens complémentaires peuvent néanmoins être inclus, notamment:Patient monitoring is carried out according to the usual procedures, but additional examinations may nevertheless be included, in particular:
- une exploration fonctionnelle respiratoire en phase pré- opératoire, c'est-à-dire avant intervention, et en phase post-opératoire, en particulier après extubation;- a respiratory functional exploration in the preoperative phase, that is to say before intervention, and in the postoperative phase, in particular after extubation;
- un enregistrement de l'électrocardiogramme jusqu'à 48 heures après intervention;- recording of the electrocardiogram up to 48 hours after surgery;
- des analyses biochimiques urinaire et sanguine.- biochemical urine and blood tests.
D'autres caractéristiques et avantages de la présente invention apparaîtront à la lumière de l'exemple de réalisation qui suit, lequel est donné à titre illustratif mais non limitatif. Exemple 1 :Other characteristics and advantages of the present invention will become apparent in the light of the embodiment which follows, which is given by way of illustration but not limitation. Example 1:
Dans l'exemple qui suit, l'efficacité du médicament selon l'invention a été mise en évidence par comparaison des résultats obtenus pour deux groupes de porcs recevant le médicament de l'invention comprenant le NO à inhaler avec ceux de deux groupes témoins ne recevant pas de NO.In the example which follows, the efficacy of the medicament according to the invention has been demonstrated by comparison of the results obtained for two groups of pigs receiving the medicament of the invention comprising the NO to be inhaled with those of two control groups not receiving no NO.
Conformément à ceci, quatre groupes de 5 porcs ont été anesthésiés et mis sous ventilation mécaniqueIn accordance with this, four groups of 5 pigs were anesthetized and put on mechanical ventilation
Le groupe 1 est le groupe témoin contrôle.Group 1 is the control group.
Le groupe 2 est le groupe témoin hypoxie dans lequel les porcs inhalent un mélange gazeux hypoxique (15% Fi02) provoquant une vasoconstriction pulmonaire et le déclenchement de réactions inflammatoires.Group 2 is the hypoxia control group in which pigs inhale a hypoxic gas mixture (15% Fi0 2 ) causing pulmonary vasoconstriction and triggering inflammatory reactions.
Le groupe 3 est le groupe recevant du NO inhalé à une concentration de 40 ppm.Group 3 is the group receiving NO inhaled at a concentration of 40 ppm.
Le groupe 4 est le groupe inhalant un mélange gazeux hypoxique contenant 40 ppm de NO.Group 4 is the group inhaling a hypoxic gas mixture containing 40 ppm NO.
Afin de permettre une évaluation des effets dûs à l'inhalation de NO, des cathéters ont été posés dans les uretères, l'aorte et la veine rénale et deux marqueurs ont été injectés en continu, il s'agit de l'inuiine et de l'acide para-amino-hippuπque La mesure de la clairance des deux marqueurs permet de calculer le débit sanguin et le taux de filtration glomérulaire. Parallèlement, le débit urinaire est également mesuré.In order to allow an evaluation of the effects due to the inhalation of NO, catheters were placed in the ureters, the aorta and the renal vein and two markers were injected continuously, they are inuiine and para-amino-hippuπque acid The measurement of the clearance of the two markers makes it possible to calculate the blood flow and the glomerular filtration rate. At the same time, urine flow is also measured.
Les résultats obtenus sont figurés dans le tableau ci-dessous.The results obtained are shown in the table below.
Groupe 1 Groupe 2 Groupe 3 Groupe 4Group 1 Group 2 Group 3 Group 4
Débit urinaire 1 0.9 1.6 1.3Urine output 1 0.9 1.6 1.3
Taux de filtration 1 1 1.9 1.2 glomérulaireFiltration rate 1 1 1.9 1.2 glomerular
Débit sanguin rénal 1 0.7 2.2 0.8Renal blood flow 1 0.7 2.2 0.8
Afin de faciliter la lecture du tableau, les valeurs des débits sanguin et urinaire, et du taux de filtration glomérulaire pour le Groupe 1 ont été volontairement fixées à 1 ; celles données pour les Groupes 2, 3 et 4 correspondent aux facteurs de corrélation.In order to facilitate the reading of the table, the values of the blood and urinary flow rates, and of the glomerular filtration rate for Group 1 were voluntarily fixed at 1; those given for Groups 2, 3 and 4 correspond to the correlation factors.
On constate que les porcs recevant du NO inhalé ont un débit urinaire, un taux de filtration glomérulaire et un débit sanguin rénal bien supérieurs aux porcs témoins contrôle.It is noted that the pigs receiving inhaled NO have a urinary flow rate, a glomerular filtration rate and a renal blood flow rate much higher than the control control pigs.
Les réactions de vasoconstriction et d'inflammation induites par l'hypoxie provoquent une diminution sensible du débit sanguin rénal. Cet effet d'hypoperfusion du rein est au moins partiellement compensé par l'inhalation du NO, qui provoque une augmentation du débit sanguin rénal, du taux de filtration glomérulaire et du débit urinaire. Cette étude confirme donc l'effet du NO inhalé, lequel permet de s'opposer aux réactions vasoconstrictrices et inflammatoires systémiques, en réduisant notamment l'adhésion des cellules circulantes. Il en découle un effet bénéfique sur les organes dits fragiles, en particulier sur les fonctions rénales, hépatiques, cardiaques, intestinales et neurologiques du patient.The hypoxia-induced vasoconstriction and inflammation reactions cause a marked decrease in renal blood flow. This effect of hypoperfusion of the kidney is at least partially offset by the inhalation of NO, which causes an increase in renal blood flow, glomerular filtration rate and urine flow. This study therefore confirms the effect of inhaled NO, which makes it possible to oppose vasoconstrictive and inflammatory systemic reactions, in particular by reducing the adhesion of circulating cells. This results in a beneficial effect on the so-called fragile organs, in particular on the renal, hepatic, cardiac, intestinal and neurological functions of the patient.
Exemple 2Example 2
Dans l'exemple qui suit, l'efficacité du médicament selon l'invention a encore une fois été mise en évidence par comparaison des résultats obtenus pour un groupe de 9 porcs recevant le médicament de l'invention comprenant le NO à inhaler avec ceux d'un groupe témoin de 7 porcs ne recevant pas de NO mais recevant plutôt de la nitroglycérine (NTG) au rythme de 40 -100 μg/kg/min.In the example which follows, the efficacy of the medicament according to the invention has once again been demonstrated by comparison of the results obtained for a group of 9 pigs receiving the medicament of the invention comprising the NO to be inhaled with those of '' a control group of 7 pigs not receiving NO but rather receiving nitroglycerin (NTG) at a rate of 40 -100 μg / kg / min.
L'expérience fut menée en quatre temps: (i) mesures physiologiques de base, (ii) phase d'hypertension pulmonaire et systémique induite par une perfusion intraveineuse de phényléphrine (iii) traitement au monoxyde d'azote ou à la nitroglycérine, (iv) phase de récupération par discontinuation de tous les traitements.The experiment was carried out in four stages: (i) basic physiological measurements, (ii) phase of pulmonary and systemic hypertension induced by an intravenous infusion of phenylephrine (iii) treatment with nitrogen monoxide or nitroglycerine, (iv ) recovery phase by discontinuation of all treatments.
Afin de permettre une évaluation des effets dûs à l'inhalation de NO, des cathéters ont été posés dans les uretères, l'aorte et la veine rénale et un marqueur fut injecté en continu. La mesure de la clairance du marqueur permettant de calculer le débit sanguin. Les résultats obtenus sont figurés dans le tableau ci-dessous.In order to allow an evaluation of the effects due to the inhalation of NO, catheters were placed in the ureters, aorta and renal vein and a marker was injected continuously. Measuring marker clearance to calculate blood flow. The results obtained are shown in the table below.
Phase i Phase ii Phase iii Phase ivPhase i Phase ii Phase iii Phase iv
NO NTG pression sanguine 1 1.55 1.60 1.47 0.95 systémique moyenne pression veineuse 1 1.70 1.28 1.29 1.08 centrale pression artérielle 1 1.36 1.15 1.13 1.05 pulmonaire moyenne pression auriculaire 1 1.97 1.38 1.25 1.20 gauche rythme cardiaque 1 0.94 1.03 1.17 1.03 débit cardiaque 1 0.93 1.02 1.08 0.95 résistance vasculaire 1 1.00 0.97 0.97 1.00 pulmonaire résistance vasculaire 1 1.65 1.45 1.05 0.99 systémiqueNO NTG blood pressure 1 1.55 1.60 1.47 0.95 systemic average venous pressure 1 1.70 1.28 1.29 1.08 central blood pressure 1 1.36 1.15 1.13 1.05 pulmonary average atrial pressure 1 1.97 1.38 1.25 1.20 left heart rate 1 0.94 1.03 1.17 1.03 heart rate 1 0.93 1.02 1.08 0.95 vascular resistance 1 1.00 0.97 0.97 1.00 pulmonary vascular resistance 1 1.65 1.45 1.05 0.99 systemic
Afin de faciliter la lecture du tableau, les valeurs des mesures pour la phase i ont été volontairement fixées à 1 ; celles données pour les phases ii, iii, et iv correspondent aux facteurs de corrélation.In order to make the table easier to read, the measurement values for phase i have been deliberately set to 1; those given for phases ii, iii, and iv correspond to the correlation factors.
Cette étude confirme à nouveau l'effet systémique du NO inhalé, lequel permet de réduire notamment la pression auriculaire gauche suggérant un effet de relaxation du ventricule gauche du muscle cardiaque. Il va de soi que la présente invention peut recevoir aménagements et variantes sans pour autant sortir du cadre de l'invention tel que définit par les revendications qui suivent. This study again confirms the systemic effect of inhaled NO, which in particular makes it possible to reduce the left atrial pressure suggesting a relaxation effect of the left ventricle of the heart muscle. It goes without saying that the present invention can receive arrangements and variants without departing from the scope of the invention as defined by the claims which follow.
Claims
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU30860/97A AU3086097A (en) | 1996-07-04 | 1997-06-18 | Nitric oxide inhalation for the prophylaxis and treatment of inflammatory response |
| EP97925805A EP0910391A1 (en) | 1996-07-04 | 1997-06-18 | Nitric oxide inhalation for the prophylaxis and treatment of inflammatory response |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2,180,506 | 1996-07-04 | ||
| CA 2180506 CA2180506C (en) | 1996-07-04 | 1996-07-04 | Inhalation of nitrogen monoxide for the prevention and the treatment of inflammatory reactions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998001142A1 true WO1998001142A1 (en) | 1998-01-15 |
Family
ID=4158540
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA1997/000428 Ceased WO1998001142A1 (en) | 1996-07-04 | 1997-06-18 | Nitric oxide inhalation for the prophylaxis and treatment of inflammatory response |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0910391A1 (en) |
| AU (1) | AU3086097A (en) |
| CA (1) | CA2180506C (en) |
| WO (1) | WO1998001142A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999045936A1 (en) * | 1998-03-10 | 1999-09-16 | L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | Supercritical conditioned gas mixture containing co2, no and optionally a neutral gas |
| WO2000030659A1 (en) * | 1998-11-23 | 2000-06-02 | Pulmonox Medical Corporation | Method and apparatus for treatment of respiratory infections by nitric oxide inhalation |
| US6793644B2 (en) | 2000-12-26 | 2004-09-21 | Sensormedics Corporation | Device and method for treatment of surface infections with nitric oxide |
| US7335181B2 (en) | 2000-12-26 | 2008-02-26 | Pulmonox Technologies Corporation | Nitric oxide decontamination of the upper respiratory tract |
| US7516742B2 (en) | 1999-11-24 | 2009-04-14 | Cardinal Health 207, Inc. | Method and apparatus for delivery of inhaled nitric oxide to spontaneous-breathing and mechanically-ventilated patients with intermittent dosing |
| US7520866B2 (en) | 2000-12-26 | 2009-04-21 | Sensormedics Corporation | Device and method for treatment of wounds with nitric oxide |
| US7531133B2 (en) | 2002-09-10 | 2009-05-12 | Pulmonox Technologies Corporation | Use of nitric oxide gas in an extracorporeal circuitry to treat blood plasma |
| JP2013519660A (en) * | 2010-02-15 | 2013-05-30 | レール・リキード−ソシエテ・アノニム・プール・レテュード・エ・レクスプロワタシオン・デ・プロセデ・ジョルジュ・クロード | Argon-based inhalable gaseous therapeutic for diseases or disorders of surrounding organs |
| RU2681123C1 (en) * | 2018-03-29 | 2019-03-04 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Method of multi-organ protection at cardiac surgical interventions accompanied by circulatory arrest |
| CN113786304A (en) * | 2021-09-28 | 2021-12-14 | 柯峰 | Application of ballast |
-
1996
- 1996-07-04 CA CA 2180506 patent/CA2180506C/en not_active Expired - Fee Related
-
1997
- 1997-06-18 WO PCT/CA1997/000428 patent/WO1998001142A1/en not_active Ceased
- 1997-06-18 AU AU30860/97A patent/AU3086097A/en not_active Abandoned
- 1997-06-18 EP EP97925805A patent/EP0910391A1/en not_active Withdrawn
Non-Patent Citations (3)
| Title |
|---|
| CHOLLET-MARTIN S ET AL: "Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 153 (3). 03-1996. 985-990., XP002042775 * |
| GUIDOT D M ET AL: "Inhaled nitric oxide prevents neutrophil-mediated, oxygen radical-dependent leak in isolated rat lungs", AMERICAN JOURNAL OF PHYSIOLOGY, 269 (1 PART 1). 1995. L2-L5., XP002042774 * |
| MALMROS C ET AL: "Nitric oxide inhalation decreases pulmonary platelet and neutrophil sequestration during extracorporeal circulation in the pig", CRITICAL CARE MEDICINE, 24 (5). 05-1996. 845-849., XP002042773 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999045936A1 (en) * | 1998-03-10 | 1999-09-16 | L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | Supercritical conditioned gas mixture containing co2, no and optionally a neutral gas |
| FR2775967A1 (en) * | 1998-03-10 | 1999-09-17 | Air Liquide | Packaged mixture of nitric oxide and carbon dioxide for use in coelioscopy - in form of supercritical fluid |
| WO2000030659A1 (en) * | 1998-11-23 | 2000-06-02 | Pulmonox Medical Corporation | Method and apparatus for treatment of respiratory infections by nitric oxide inhalation |
| US7516742B2 (en) | 1999-11-24 | 2009-04-14 | Cardinal Health 207, Inc. | Method and apparatus for delivery of inhaled nitric oxide to spontaneous-breathing and mechanically-ventilated patients with intermittent dosing |
| US6793644B2 (en) | 2000-12-26 | 2004-09-21 | Sensormedics Corporation | Device and method for treatment of surface infections with nitric oxide |
| US7335181B2 (en) | 2000-12-26 | 2008-02-26 | Pulmonox Technologies Corporation | Nitric oxide decontamination of the upper respiratory tract |
| US7520866B2 (en) | 2000-12-26 | 2009-04-21 | Sensormedics Corporation | Device and method for treatment of wounds with nitric oxide |
| US7531133B2 (en) | 2002-09-10 | 2009-05-12 | Pulmonox Technologies Corporation | Use of nitric oxide gas in an extracorporeal circuitry to treat blood plasma |
| JP2013519660A (en) * | 2010-02-15 | 2013-05-30 | レール・リキード−ソシエテ・アノニム・プール・レテュード・エ・レクスプロワタシオン・デ・プロセデ・ジョルジュ・クロード | Argon-based inhalable gaseous therapeutic for diseases or disorders of surrounding organs |
| RU2681123C1 (en) * | 2018-03-29 | 2019-03-04 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Method of multi-organ protection at cardiac surgical interventions accompanied by circulatory arrest |
| CN113786304A (en) * | 2021-09-28 | 2021-12-14 | 柯峰 | Application of ballast |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3086097A (en) | 1998-02-02 |
| CA2180506C (en) | 2003-11-25 |
| CA2180506A1 (en) | 1998-01-05 |
| EP0910391A1 (en) | 1999-04-28 |
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