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WO2024223950A1 - Propanediols mono- et bis-nitrosylés destinés à être utilisés dans le traitement d'une maladie thromboembolique - Google Patents

Propanediols mono- et bis-nitrosylés destinés à être utilisés dans le traitement d'une maladie thromboembolique Download PDF

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Publication number
WO2024223950A1
WO2024223950A1 PCT/EP2024/061806 EP2024061806W WO2024223950A1 WO 2024223950 A1 WO2024223950 A1 WO 2024223950A1 EP 2024061806 W EP2024061806 W EP 2024061806W WO 2024223950 A1 WO2024223950 A1 WO 2024223950A1
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compound
nmol
arterial
formula
use according
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Inventor
Per Håkan AGVALD
Leif Christofer ADDING
Kristofer Bo Ingemar NILSSON
Anna STENE HURTSÉN
Magnus GRENEGÅRD
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Attgeno AB
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Attgeno AB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to methods of treating a condition, wherein such treatment comprises administering certain mono- and/or bis-nitrosylated propanediols, including compositions and formulations thereof, and wherein said administration is to a patient in need thereof via intra-arterial infusion in a dose of from about 0.01 to 3000 nmol kg 1 min- i
  • the present invention also relates to the use of mono- and/or bis-nitrosylated propanediols for treating thromboembolic disease.
  • Organ ischemia, dysfunction and failure after major surgery and in critical illness are devastating complications causing significant comorbidity and mortality.
  • a specific medical therapy targeted to treat the ischemia e.g. increasing blood flow by vasodilation, enhanced collateral blood flow, avoiding local formation of microthrombi/emboli by platelet inhibition, reducing reperfusion injury by inhibiting oxygen radical production
  • uncontrolled activation of platelets is a key pathological event in acute thromboembolism, vessel occlusion and ischemic tissue damage, including mechanisms of thromboinflammation and immune-thrombosis.
  • Pulmonary embolism represents a disease condition in which the interplay between several vital components are represented: cardiovascular and respiratory systems, inflammation and coagulation.
  • ischemia is those conditions caused by acute arterial occlusion, which is a medical emergency where the damage caused depends on how long the affected organ will tolerate ischemia, which is a few minutes in the brain and roughly 4-6 hours in a limb.
  • Symptoms of arterial occlusion include pain and loss of function. The longer these symptoms are present, the less likely it is to salvage the organ.
  • Dissolving or removing a blood clot to revascularize tissue is crucial.
  • Nitric oxide (NO) is a molecule of importance in several biological systems. It has become generally recognised that endogenous NO is of critical importance as a mediator of vasodilation in blood vessels.
  • NO-donors have been in use since the mid-19th century to treat heart disease, the most well-known being nitroglycerin.
  • problems with currently available NO donors including tolerance development and the risk of side effects attributed to the release of NO throughout the entire circulatory system.
  • these problems with currently available NO donors including tolerance development and the risk of side effects attributed to the release of NO throughout the entire circulatory system.
  • this usefulness of current available NO donors is restricted since when increasing the dose of existing NO- donors the vasodilatory effect elicited could cause dangerous drop in blood pressure when vessels in the entire vascular system is widened by the NO released.
  • nitrates in a clinical setting are presently used to treat the symptoms of angina (chest pain).
  • Organic nitrates work by relaxing blood vessels and increasing the supply of blood and oxygen to the heart while reducing its workload.
  • examples of presently available organic nitrate drugs include: a) Nitroglycerin (glyceryl trinitrate) (1,2,3-propantriol-nitrate), which is today mostly taken sublingually to curb an acute attack of angina.
  • strong headaches and dizziness due to the rapid and general vasodilatory effect are frequently encountered side-effects.
  • Nitroglycerin infusion concentrates are also available and are diluted in isotonic glucose or physiological saline for intravenous infusion.
  • Tolerance development i.e. diminished efficacy with repeated or continuous dosage
  • Isosorbide mononitrate l,4:3,6-dianhydro-D-glucitol-5-nitrate
  • Tolerance development is a problem in longterm treatment regimens. Frequent side-effects include headache and dizziness, as encountered with nitroglycerin.
  • Pentaerythrityl nitrates a group of organic nitrates, which are known to exert longterm antioxidant and anti-atherogenic effects by currently unidentified mechanisms. Pentaerythrityl tetranitrate has been investigated in the context of nitrate tolerance, an unwanted development in nitrate therapy, and experimentally tested in pulmonary hypertension.
  • glyceryl trinitrate, ethyl nitrite, isobutyl nitrate, isobutyl nitrite, isoamyl nitrite and butyl nitrite have been tested in a rabbit model and were found to give a significant correlation between the in vivo generation of NO and effects on blood pressure (Cederqvist et al., Biochem. Pharmacol., 1994, 47, 1047-53).
  • compositions and methods for use in the therapeutic delivery of gaseous nitric oxide comprise a compound capable of forming a reversible bond or association to NO, such as alcohols, carbohydrates and proteins.
  • WO 2007/106034 describes methods for producing organic nitrites from a compound which is a mono/polyhydric alcohol, or an aldehyde- or ketone-derivate thereof.
  • the methods involve the de-aeration of an aqueous solution of said compound, followed by purging with gaseous nitric oxide (NO).
  • NO gaseous nitric oxide
  • Nilsson, K. F. et al., Biochem Pharmacol., 82(3), 248-259 (2011) discusses the formation and identification of new bioactive organic nitrites.
  • WO 2020/109420 describes processes for making mono- and/or bis-nitrosylated propanediols along with the resulting compositions prepared. This document explains that such compounds are capable of treating conditions where NO has a beneficial effect.
  • WO 2021/239906 describes how these compounds have surprisingly been shown to be effective in treating microbial infections.
  • PDNO mono- and/or bis-nitrosylated propanediols
  • the effectiveness of these could be influenced by the local environment in the organs where the NO liberation from the molecules occur such as local pH, the levels of oxygen and carbon dioxide, state of inflammation in the tissue etc.
  • the bioavailability of the NO released by a specific NO-donor might vary due to various factors such as the concentration of oxygen radicals in the tissues, which in turn could be influenced by the metabolism of the NO donors per se, i.e. the release of NO from nitroglycerin has been shown to increase the levels of oxygen radicals which in turn might contribute to tissue damage.
  • Organic mononitrites of 1,2-propanediol act as an effective NO-releasing vasodilator in pulmonary hypertension and exhibit no cross-tolerance with nitroglycerin in anesthetized pigs.
  • kidneys or a specific kidney
  • part of the intestine has not been studied. Nor has the relationship between such changes in flow in relation to effects on the systemic blood pressure and/or cardiac output been measured. The reason for such studies not being performed is they are not a natural continuation of the developmental program for exploring the role of PDNO in the lung blood circulation and the general systemic circulation. The findings regarding these presented herein are astonishing since there was not even any motivation provided by the general development program to investigate this route and with an entirely different focus the previous studies could not be extrapolated to the inventions described herein.
  • the present inventors were surprised by the potency and effects of PDNO degradation discovered when intraarterial infusions were tested. That is the inventors were surprised by the fast onset of release of nitric oxide that induces the beneficial effects without having the PDNO passing the pulmonary circulation first. What is even more surprising was that the dose in which PDNO could be given and the magnitude of the response in the vessels of the brain, limbs, kidneys and intestine was unexpected when compared to the dosing possible when administered intravenously in that local treat whilst avoiding, or reducing, systemic effects. The present inventors were also surprised that a lower dose was required by intraarterial administration to achieve an effect versus intravenous administration. The present inventors were further surprised that at higher doses administered intraarterially that did affect the systemic blood pressure these had a pronounced effect on blood flow over the specific target organs, where they had expected the local effect to lessen due to the decrease in driving pressure.
  • the invention also includes the surprising finding that PDNO in experiments performed could elicit antithrombotic effects. To be able to achieve this NO has to be delivered in a sufficient amount to enter into the thrombocytes. Given that the platelets are surrounded by red blood cells filled with haemoglobin, normally acting as a sink for NO which in blood has been shown to have a biological half-life in the milli second range, it exceptional that PDNO in spite of this seem to affect the platelet function even in considerable low doses. Whether this means that in from PDNO is released within the platelets or if this is accomplished by another unknown mechanism is unclear. However, the combined targeted local vasodilatory and antithrombotic effects of PDNO is surprising and is of potential great value in treatments of several forms of tissue ischemia.
  • the present inventors have unexpectedly found that administering certain mono- and/or bis-nitrosylated propanediols, including compositions and formulations thereof, to a patient in need thereof via intra-arterial infusion at certain doses is able to achieve local, site-specific, treatment of conditions, particularly those conditions where NO is expected to have a beneficial effect, whilst avoiding unwanted systemic side effects.
  • a compound of formula (I) wherein R 1 , R 2 and R 3 each independently represent H or -NO, wherein n is 0 or 1; wherein when n is 0, R 1 is H; and wherein when n is 1, R 2 is H, provided that at least one of R 1 R 2 and R 3 represents -NO, for use in the treatment of a condition, wherein the compound of formula (I) is administered to a patient in need thereof via intra-arterial infusion at a dose of from about 0.01 to 3000 nmol kg 1 min -1 , which method is referred to herein as "the first method of the invention".
  • the terms "consists essentially of” and “consisting essentially of” will refer to the relevant component being formed of at least 80% (e.g. at least 85%, at least 90%, or at least 95%, such as at least 99%) of the specified substance(s), according to the relevant measure (e.g. by weight thereof).
  • the terms “consists essentially of” and “consisting essentially of” may be replaced with “consists of” and “consisting of”, respectively.
  • references to the treatment of a particular condition take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity of one or more clinical symptoms and/or signs associated with the condition.
  • the term may refer to achieving reduction in the severity of chest pain, shortness of breath and/or pulmonary hypertension via vasodilation.
  • the term may also refer to achieving pulmonary vasodilation or a decrease in pulmonary vascular resistance and right ventricular strain.
  • references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients.
  • patient may refer to a human subject.
  • patient may also refer to animals (e.g. mammals), such as household pets (e.g. cats and, in particular, dogs), livestock and horses.
  • the method according to the invention comprises administering to a patient in need thereof an effective amount of a compound according to formula (I).
  • an effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • the compound of formula (I) may be administered at a dose of from about 0.01 to about 300 nmol kg 1 min -1 , for example from about 1 to about 300 nmol kg -1 min -1 , such as from about 1 to about 100 nmol kg -1 min -1 , or from about 10 to about 3000 nmol kg -1 min -1 , such as 10 to about 300 nmol kg -1 min -1 .
  • the compound of formula (I) is administered in a dose of from about 1 to about 30 nmol kg -1 min -1 .
  • the compound of formula (I) may be administered in a dose of from about 1 to less than about 30 nmol kg -1 min -1 , such as about 1 to about 25, 26, 27, 28 or 29 nmol kg -1 min -1 , for example from about 1 to about 20 nmol kg -1 min -1 , about 1 to about 15, 14, 13, 12 or 11 nmol kg -1 min -1 , such as from about 1 to about 10 nmol kg -1 min -1 .
  • the compound of formula (I) may be administered continuously, such as continuous infusion, and this may occur for a time period of up to 14 days, such as 7 days.
  • the compound of formula (I) may alternatively be administered in a single dose, or in repeated single shots, such as in a bolus infusion.
  • the compound of formula (I) may be administered to any part of the arterial vasculature that is accessible to the medical professional to deliver the compound of formula (I) by infusion.
  • the infusion may be achieved by a surgical technique, such as through use of a catheter apparatus.
  • the intra-arterial administration may be with the aim to deliver the compound according to formula (I) to the lower limb and this may be achieved by intra-arterial administration to the femoral artery.
  • the intra-arterial administration may also, or alternatively, be with the aim to deliver the compound according to formula (I) to the brain and this may be achieved by intra-arterial administration to the carotid artery.
  • the intra-arterial administration may further, or alternatively, be with the aim to deliver the compound according to formula (I) to the intestine and this may be achieved by intraarterial administration to the superior mesenteric artery.
  • the intra-arterial administration may further, or alternatively, be with the aim to deliver the compound according to formula (I) to the kidney, the adrenal gland and/or the ureter and this may be achieved by intra-arterial administration to the renal artery.
  • the compound of formula (I) may, therefore, be administered via intra-arterial infusion to the femoral artery, the carotid artery, the superior mesenteric artery, the splenic artery, the hepatic artery and/or the renal artery.
  • the compound of formula (I) When the compound of formula (I) is administered via intra-arterial infusion to the femoral artery and/or the carotid artery, it may be administered at a dose of from about 1 to about 300 nmol kg 1 min -1 , such as 1 to about 60 nmol kg -1 min -1 , for example 1 to about 50 nmol kg -1 min i, such as 1 to about 30 nmol kg -1 min -1 .
  • the compound of formula (I) When the compound of formula (I) is administered via intra-arterial infusion to the superior mesenteric artery, it may be administered at a dose of from about 3 to about 3000 nmol kg -1 min -1 , such as from about 30 to about 1000 nmol kg -1 min -1 , for example from about 100 to about 1000 nmol kg -1 min -1 .
  • the compound of formula (I) When the compound of formula (I) is administered via intra-arterial infusion to the renal artery, it may be administered at a dose of from about 0.01 to about 300 nmol kg -1 min -1 , for example from about 1 to about 30 nmol kg -1 min -1 .
  • this is intended to also include administering to an arterial branch that leads from that artery.
  • the administration could be to the superficial epigastric artery, superficial circumflex artery, the external pudendal artery, the deep femoral (or profunda femoris) artery or the superficial femoral artery, which all are connected to the femoral artery.
  • this may be via cerebral arteries, i.e. circulus willisi.
  • the condition to be treated according to the first method of the invention may be one wherein NO has a beneficial effect. That is to say, the compounds according to formula (I) are useful in the treatment of a condition wherein NO, i.e. administration of NO, has a beneficial effect.
  • the term "beneficial effect” means that the use/administration of the compounds/compositions of the invention leads to an identifiable treatment, and/or improvement, of the condition in the patient being treated.
  • the beneficial effect may be temporary or permanent and may be measured or determined by a medical practitioner or by the patient themselves.
  • a particular result of the present invention is that the beneficial effect may be experienced locally, e.g. just in one organ of the patient, but not have a clinically significant systemic effect.
  • the beneficial effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • the condition to be treated may be selected from the group consisting of: acute pulmonary vasoconstriction of different genesis; pulmonary hypertension of different genesis, including primary hypertension and secondary hypertension; preclampsia; eclampsia; conditions of different genesis in need of vasodilation; erectile dysfunction; systemic hypertension of different genesis; regional vasoconstriction of different genesis; local vasoconstriction of different genesis; acute heart failure (with or without preserved ejection fraction (HFpEF)); coronary heart disease; myocardial infarction; ischemic heart disease; angina pectoris; instable angina; cardiac arrhythmia; acute pulmonary hypertension in cardiac surgery patients; acidosis; inflammation of the airways; cystic fibrosis; COPD; immotile cilia syndrome; inflammation of the lung; pulmonary fibrosis; acute lung injury (ALI); adult respiratory distress syndrome; acute pulmonary oedema; acute mountain sickness; asthma; bronchitis;
  • condition to be treated may be pulmonary hypertension of different genesis, including primary hypertension and secondary hypertension.
  • Particular conditions that may be include those selected from the group consisting of ischemic diseases of different genesis; thromboembolic diseases including diseases that are complicated by thromboembolism, such as various blood diseases; arterial thrombosis; peripheral ischemia (limb ischemia); thromboembolic stroke; pulmonary embolism; acute mesenteric ischemia (mesenteric arterial occlusion); acute renal artery occlusion; arterial stenosis; arterial occlusion; infarction of the spleen; infarction of the liver, infarction of the lung; Kawasaki disease; and arterial embolism.
  • ischemic diseases of different genesis thromboembolic diseases including diseases that are complicated by thromboembolism, such as various blood diseases; arterial thrombosis; peripheral ischemia (limb ischemia); thromboembolic stroke; pulmonary embolism; acute mesenteric ischemia (mesenteric arterial occlusion); acute renal artery occlusion; arterial stenos
  • ischemic diseases With regard to the treatment of ischemic diseases, it is to be understood that this includes the treatment/prophylaxis of conditions arising from arterial occlusions (partial or full), which result in restricted flow to a specific organ and ischemia or threatening ischemia.
  • the treatment may be manifest by a decline in mean systemic arterial pressure (MAP) of no greater than about 10% relative to the MAP baseline in the subject prior to treatment.
  • MAP mean systemic arterial pressure
  • the treatment may be manifest by a decline in MAP of no greater than about 9%, 8%, 7%, or 6% relative to the MAP baseline in the subject prior to treatment.
  • the treatment may be manifest by a decline in MAP of no greater than about 5% relative to the MAP baseline in the subject prior to treatment.
  • the treatment may be manifest by a decline in end-tidal NO (ETNO) of no greater than about 10% relative to the ETNO baseline in the subject prior to treatment.
  • ETNO end-tidal NO
  • the treatment may be manifest by a decline in ETNO of no greater than about 9%, 8%, 7%, or 6% relative to the ETNO baseline in the subject prior to treatment.
  • the treatment may be manifest by a decline in ETNO of no greater than about 5% relative to the ETNO baseline in the subject prior to treatment.
  • the treatment may be manifest by an increase in methemoglobin fraction in the blood of no greater than about 10% relative to the methemoglobin fraction baseline in the subject prior to treatment.
  • the treatment may be manifest by an increase in methemoglobin fraction in the blood of no greater than about 9%, 8%, 7%, or 6% relative to the methemoglobin fraction baseline in the subject prior to treatment.
  • the treatment may be manifest by an increase in methemoglobin fraction in the blood of no greater than about 5% relative to the methemoglobin fraction baseline in the subject prior to treatment.
  • relative to the baseline level we refer to the comparison between the measured MAP level at the beginning of the study (i.e. prior to administration of the compound of formula (I)) to the MAP level following administration.
  • the baseline level is the level immediately prior to the start of the treatment and is used as a comparator for subsequently measured levels (e.g. immediately following a course of treatment, or at a timepoint following conclusion of a course of treatment).
  • subsequently measured levels e.g. immediately following a course of treatment, or at a timepoint following conclusion of a course of treatment.
  • Such a comparison is specific for the subject or group of subjects in question and is not an absolute value.
  • Further particular conditions that may be treated include bacterial, fungal, viral or parasitic infections.
  • the present inventors have further unexpectedly found that administering certain mono- and/or bis-nitrosylated propanediols, including compositions and formulations thereof, to a patient in need thereof is particularly effective in inhibiting platelet aggregation, which is useful in the treatment of thromboembolic disorders.
  • a compound of formula (I) wherein R 1 , R 2 and R 3 each independently represent H or -NO, wherein n is 0 or 1; wherein when n is 0, R 1 is H; and wherein when n is 1, R 2 is H, provided that at least one of R 1 R 2 and R 3 represents -NO, for use in the treatment of thromboembolic disease, which is referred to herein as "the second method of the invention".
  • Thromboembolic diseases are those that are caused when a blood clot that forms in a blood vessel breaks loose, is carried by the bloodstream, and leads to blocking a blood vessel, at least partially.
  • the thromboembolic disease that is to be treated may be selected from the group consisting of arterial thrombosis; myocardial infarction; cerebral venous thrombosis; portal vein thrombosis; peripheral ischemia (limb ischemia); thromboembolic stroke; pulmonary embolism; acute mesenteric ischemia (mesenteric arterial occlusion); acute renal artery occlusion; arterial stenosis; arterial occlusion; venous thromboembolism, including deep vein thrombosis; and arterial embolism.
  • Thromboembolic diseases occur both in the venous system and the arterial system and, for the avoidance of doubt, it is envisaged that the use of the compound according to formula (I) in the treatment of such diseases encompasses both venous and arterial treatment. Therefore, the compound according to formula (I) may be administered via intravenous and/or intraarterial infusion.
  • the treatment may occur through other routes of administration, such routes include inhalation, nebulisations, intramuscular administration, subcutaneous administration, transdermal administration, intranasal administration, sublingual administration, subconjunctival administration, rectal administration, endotracheal administration, pulmonary administration, gastric administration, ureteral administration, enteral administration, uretheral administration, vesical administration, buccal administration and enteral administration.
  • routes of administration include inhalation, nebulisations, intramuscular administration, subcutaneous administration, transdermal administration, intranasal administration, sublingual administration, subconjunctival administration, rectal administration, endotracheal administration, pulmonary administration, gastric administration, ureteral administration, enteral administration, uretheral administration, vesical administration, buccal administration and enteral administration.
  • the compound according to formula (I) may be administered at a dose of from about 0.01 to 3000 nmol kg -1 min -1 , such as from about 0.01 to about 300 nmol kg -1 min -1 , for example from about 1 to about 300 nmol kg -1 min -1 , such as from about 1 to about 100 nmol kg 1 min -1 .
  • the compound of formula (I) is administered in a dose of from about 1 to about 30 nmol kg -1 min -1 .
  • the compound of formula (I) may be administered in a dose of from about 1 to less than about 30 nmol kg -1 min -1 , such as about 1 to about 25, 26, 27, 28 or 29 nmol kg -1 min -1 , for example from about 1 to about 20 nmol kg -1 min -1 , about 1 to about 15, 14, 13, 12 or 11 nmol kg -1 min -1 , such as from about 1 to about 10 nmol kg -1 min -1 .
  • the compound of formula (I) may be administered in a dose of from about 1 to about 5 nmol kg -1 min -1 .
  • the compound according to formula (I) may be administered in any way into the vasculature, such as via intra-arterial infusion into any artery of any limb.
  • the compound according to formula (I) may be administered via intra-arterial infusion, such as to the femoral artery, the carotid arterial, the renal artery or the superior mesenteric artery.
  • the compound according to formula (I) may be administered via intra-venous infusion, such as to the central venous system, peripheral veins in the arms and legs, femoral veins and scalp veins (particularly scalp veins in neonatals).
  • Intra-venous infusion may also be to deep or superficial veins, such as varicose superficial veins in the leg.
  • the treatment may be manifest by an increase in methemoglobin fraction in the blood of no greater than about 10% relative to the methemoglobin fraction baseline in the subject prior to treatment.
  • the treatment may be manifest by an increase in methemoglobin fraction in the blood of no greater than about 9%, 8%, 7%, or 6% relative to the methemoglobin fraction baseline in the subject prior to treatment.
  • the treatment may be manifest by an increase in methemoglobin fraction in the blood of no greater than about 5% relative to the methemoglobin fraction baseline in the subject prior to treatment.
  • relative to the baseline level we refer to the comparison between the measured MAP level at the beginning of the study (i.e. prior to administration of the compound of formula (I)) to the MAP level following administration.
  • the baseline level is the level immediately prior to the start of the treatment and is used as a comparator for subsequently measured levels (e.g. immediately following a course of treatment, or at a timepoint following conclusion of a course of treatment).
  • subsequently measured levels e.g. immediately following a course of treatment, or at a timepoint following conclusion of a course of treatment.
  • the inhibition of platelet aggregation appears to occur by a surprising method that is different to other treatments and proceeds by inhibition of releasing platelet granula and ATP release.
  • the second method of the invention also encompasses a method of inhibiting platelet granula release and/or ATP release in a subject, said method comprising administering an effective amount of one or more compounds of Formula (I), or a pharmaceutical formulation thereof, to a subject in need thereof.
  • This aspect of the invention may comprise any of the features outlined above in respect of the treatment of thromboembolic disease.
  • a particular compound for use in both the first and second method of the invention is a compound according to formula (II) wherein R 2 and R 3 each independently represent H or -NO, provided that at least one of R 2 and R 3 represents -NO.
  • the compounds of formula (I) may contain an asymmetric carbon atom as outlined above and will therefore exhibit optical isomerism.
  • a further particular compound for use in both the first and second method of the invention is a compound according to formula (III): wherein R 1 and R 3 each independently represent H or -NO, provided that at least one of R 1 and R 3 represents -NO.
  • a further particular compound for use in both the first and second method of the invention is a compound according to formula (IV): wherein R 4 and R 5 each independently represent H or -NO, provided that at least one of R 4 and R 5 represents -NO.
  • the compound for use in both the first and second method of the invention may be present in a composition comprising:
  • compositions (b) one or more corresponding compounds of formula (I) but wherein R 1 , R 2 and R 3 represent H (e.g. 1,2-propanediol and/or 1,3-propanediol), which compositions may be referred to hereinafter as "the composition".
  • composition may be substantially non-aqueous.
  • references to "substantially non-aqueous" will refer to the component comprising less than 10%, for example less than 9.9%, 9%, 8%, 7%, 6%, 5%, 4% 3%, 2% or 1% (such as less than 0.5% or less than 0.1%, e.g. less than 0.05%, less than 0.01%) by weight of water.
  • composition may comprise a mixture of compounds falling within formula (I).
  • Particular compositions that may be mentioned include those wherein the composition comprises from about 0.01% to about 9% (e.g. about 0.01% to about 5%, such as about 3% to about 5%, or about 5% to about 7%) by weight of the one or compound of formula (I).
  • compositions that may be mentioned include those wherein the composition comprises from about 1 to about 1000 mM (e.g. about 5 to about 750 mM, such as about 5 to about 500 mM, or about 10 to about 203mM) of the one or more compound of formula (I).
  • mM e.g. about 5 to about 750 mM, such as about 5 to about 500 mM, or about 10 to about 203mM
  • the unit mM refers to the concentration of the compound of formula (I) in the composition in IO -3 mol/L and, where the composition comprises a mixture of compounds of formula (I), is based on the average molecular weight of the compounds of formula (I) in the composition.
  • compositions that may be mentioned include those wherein the composition comprises a compound according to formula (II).
  • the compound according to formula (II) is the S form.
  • the S form of the compound according to formula (II) is preferred as this has a higher rate of metabolism, and a different metabolic pathway, than the R form. Furthermore, the S form has a different metabolic degradation route, which results in metabolites which are less toxic than those from the R form.
  • compositions that may be mentioned include those wherein the composition comprises a compound according to formula (III).
  • the compound according to formula (II) is the S form, although it is envisaged that the product is a mixture of both the S and R form of formula (II) with the S form preferably being present in an enantiomeric excess (ee).
  • the compound according to formula (II) may be in an enantiomeric excess of the S form of the compound. That is to say, greater than 50 ee% of the product is in the S form, such as greater than, or equal to, 60 ee%, 70 ee%, 80 ee%, 90 ee%, 95 ee% or 98 ee% of the product is the S form.
  • the product is a mono-nitrosylated compound according to formula (II)
  • greater than 50 wt.% of the product is nitrosylated in the 2 position (i.e. R 2 is -NO), such as between about 55 wt.% and about 80 wt.% is nitrosylated in the 2 position, for example between about 55 wt.% and 75 wt.%.
  • compositions that may be mentioned include those wherein the composition consists essentially of one or more compounds of formula I and corresponding compounds of formula I but wherein R 1 , R 2 and R 3 represent H (i.e. 1,2-propanediol and/or 1,3- propanediol).
  • compositions may comprise (or, particularly, consist essentially of or, more particularly, consist of) one or more compounds of formula II and 1,2-propanediol.
  • compositions may comprise (or, particularly, consist essentially of or, more particularly, consist of) one or more compounds of formula III and 1,3-propanediol.
  • compositions that may be mentioned include those wherein the composition comprises (or, particularly, consists essentially of or, more particularly, consists of) one or more compounds of formula (II) and (III) along with 1,2-propanediol and 1,3-propanediol.
  • compositions that may be mentioned include those wherein the composition is substantially free of dissolved nitric oxide.
  • compositions comprise less than 5 wt. %, 4 wt. %, 3 wt.%, 2 wt.% or 1 wt.% of dissolved nitric oxide, such as less than 0.5 wt.% or 0.1 wt.%.
  • compositions may comprise:
  • compositions may be administered alone or may be administered by way of known pharmaceutical compositions/formulations.
  • composition may be comprised in a pharmaceutical formulation, optionally wherein the pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients.
  • references herein to pharmaceutical formulations herein refer to the composition in the form of a pharmaceutical formulation and will include references to all embodiments and particular forms thereof.
  • the term pharmaceutically-acceptable excipients includes references to vehicles, adjuvants, carriers, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, permeability enhancers, wetting agents and the like.
  • excipients may include adjuvants, diluents or carriers.
  • compositions that may be mentioned include those wherein the pharmaceutical formulation comprises at least one pharmaceutically acceptable excipient.
  • compositions that may be mentioned include those wherein the one or more pharmaceutically acceptable excipients are substantially non-aqueous.
  • the compound according to Formula (I) may be administered to a patient (i.e. a subject) in conjunction with a suitable aqueous buffer, such as a non-nucleophilic and weakly basic buffer.
  • a suitable aqueous buffer such as a non-nucleophilic and weakly basic buffer.
  • the buffer has a pH of from about 7.1 to about 10 (e.g. about 8 or about 9.2), such as a carbonate (e.g. NaHCC ) buffer or a phosphate buffer, or a mixture thereof.
  • a carbonate (e.g. NaHCC ) buffer or a phosphate buffer or a mixture thereof.
  • the buffer may be a carbonate buffer with pH 9.2 or a phosphate buffer with pH 8.0 (e.g. a 0.154 molar buffer), or a NaHCCh buffer with pH 8.0.
  • a carbonate buffer with pH 9.2 or a phosphate buffer with pH 8.0 (e.g. a 0.154 molar buffer), or a NaHCCh buffer with pH 8.0.
  • Figure 1 Study protocol of dose-response experiments of intravenous and organ-directed intraarterial infusions of 1,2 propanediol organic mononitrites (PDNO) in the carotid and femoral artery (panel A) as well as renal and superior mesenteric artery (panel B).
  • PDNO 1,2 propanediol organic mononitrites
  • Figure 2 Effects of organ-directed intraarterial infusion of 1,2 propanediol organic mononitrites (PDNO) and intravenously administered PDNO on regional blood flow, mean systemic arterial pressure (MAP) and end-tidal nitric oxide concentrations (ETNO) in the left carotid artery (panel A and B) and left common femoral artery (panel C and D). Data are mean with standard error of the mean (SEM). * denotes statistical significance (P ⁇ 0.05) from baseline (BL) in femoral and carotid intraarterial experiments. * represents statistical significance (P ⁇ 0.05) from BL during intravenous administration.
  • MAP mean systemic arterial pressure
  • ENO end-tidal nitric oxide concentrations
  • Figure 3 Effects of organ-directed infusion of 1,2 propanediol organic mononitrites (PDNO) and intravenously administered PDNO on regional blood flow, mean systemic arterial pressure (MAP) and end-tidal nitric oxide (ETNO) in the superior mesenteric artery (SMA, panel A and B) and left renal artery (panel C and D). Data are mean with standard error of the mean (SEM). *denotes statistical significance (p ⁇ 0,05) from baseline (BL) in renal intraarterial experiments and from vasopressin (VP) in SMA experiments. * represents statistical significance (p ⁇ 0,05) from BL during intravenous administration.
  • SEM standard error of the mean
  • FIG. 4 Dose ratio calculations of end-tidal nitric oxide (ETNO) between intravenous administration of 1,2 propanediol organic mononitrites (PDNO) and intraarterial administration in the left common femoral, left common carotid, left renal and superior mesenteric artery.
  • ETNO Bo e Bldose (panel A) and natural logarithmized ETNO for linearization
  • In ETNO Bi dose + In Bo (panel B).
  • Estimated coefficients and standard errors panel C).
  • Figure 5 The arterial fraction of methemoglobin during organ-directed intraarterial infusion of 1,2 propanediol organic mononitrites (PDNO) and intravenously administered PDNO. Data are mean with standard error of the mean (SEM).
  • the blood was stimulated with the PAR-1 agonist peptide SFLLRN and platelet aggregation (registered as increases in electrical resistance) was followed over a period of 10 min.
  • Data are individual values and median (the lines).
  • the P-value is from analysis with Dunn's test.
  • Figure 9 Increases in Ser 239-specific VASP phosphorylation in platelets.
  • Suspensions of isolated human blood platelets were stimulated by either PDNO or nitroglycerine.
  • the platelets were exposed to the NO-donors for 5 min followed by Western immuno blotting for phosphoVASP detection.
  • These experiments were conducted in unstimulated and SFLLRN-stimulated platelets.
  • the PAR-1 agonist was added 2 min after PDNO/nitroglycerine.
  • PDNO 1,2 propanediol mono-organic nitrites
  • P values indicate the difference between the groups. Data presented as mean ⁇ standard error of the mean.
  • MAP mean systemic arterial blood pressure
  • ETNO End-tidal nitric oxide level
  • Example 1 Composition
  • a composition comprising a mixture of 1- (nitrosooxy)propan-2-ol and 2-(nitrosooxy)propan-l-ol (which mixture is referred to herein as PDNO) along with 1,2 -propane diol (PD; or propylene glycol) was used.
  • the composition contained 6.5 to 7.1 w/w% PDNO, with the balance being propylene glycol.
  • compounds of formula (I) may also be referred to herein may be referred to by the acronym PDNO, which will indicate that such compounds, including all embodiments and particular features thereof, are used in the methods and uses as described in relation to the present invention.
  • the PD refers to the corresponding propanediol to the compound of formula (I), that is to say the PD is the same compound according to formula (I), but wherein but wherein R 1 , R 2 and R 3 represent H.
  • PDNO is an ultra-fast-releasing with a very short half-life, however, half-life has never been determined.
  • the aim of this study was to compare intraarterial infusion of PDNO with iv infusions regarding local organ blood flow and systemic effects, and to estimate the in vivo half-life of PDNO. A summary of this study is provided below with a detailed methodology following.
  • MAP mean systemic arterial pressure
  • ETNO end-tidal nitric oxide
  • the in vivo half-life was estimated to 5.5-6.1 s (infusions) and 3.0-3.9 s (injections).
  • Organ-directed intraarterial (CCA, CFA and SMA) infusions of PDNO increased organspecific blood flow dose-dependently, with no or minor systemic effects at effective doses, in contrast to RA and iv infusions.
  • CCA, CFA and SMA Organ-directed intraarterial infusions of PDNO
  • ETNO concentration There was a substantial right-shift of the doseresponse effects on ETNO concentration when comparing intraarterial and iv infusions probably due to rapid decomposition of PDNO in blood.
  • the in vivo half-life of PDNO was estimated to be in the range of 3.0-6.1 s.
  • the femoral arteries and the common carotid arteries were provided with flow probes (3 mm, Transonic System Inc., NY, USA).
  • An angiographic catheter (Soft-Vu Berenstein 5Fr, Queensbury, NY. USA or SOFT-VU Sos Omni® selective 5 Fr, Queensbury NY USA) was positioned in the left carotid or left femoral artery via the 5 Fr introducer (Cordis Corportation, USA) in right brachial artery using a guide wire (Terumo Radiofocus ® STIFF type angles 0.035, Terumo corporation TOKYO, Japan). Location was confirmed with angiography.
  • a microcatheter (Terumo Progreat®, 2.7 Fr.
  • PDNO was repeatedly injected via the microcatheter in the left common femoral (1-4 micromol), left carotid artery (0.5-2 micromol) and the CVC in superior caval vein (0.5-4 micromol). In addition, 10 ml of 5% sodium bicarbonate solution was injected at these sites.
  • the renal arteries were provided with 3 mm flow probes (Transonic System, USA) through a retroperitoneal incision and the SMA was enclosed with a 6 mm flow probe (Transonic System, USA) through laparotomy.
  • the targeted arteries were provided with a microcatheter (RebarTM-18 Micro Catheter, Microtherapeutics, Inc., CA, USA) in a similar manner as previously described, with the angiographic catheter withdrawn to the aorta in both renal and SMA experiments.
  • PDNO was infused using syringe pumps with a carrier solution (bicarbonate 1.4%) and administered via the microcatheter at eight doses (0.01, 0.1, 1, 3, 10, 30, 100 and 300 nmol kg 1 min -1 , 20 minutes per dose) in the left common femoral and left carotid artery, block randomization was applied (figure 1A (carotid and femoral artery) and figure IB (renal and superior mesenteric artery)). Between the local intraarterial infusion routes, intravenous infusions in the central venous catheter at four doses (3, 10, 30 and 100 nmol kg -1 min -1 , 10 minutes per dose) were given for reference. There was a washout period of 60 minutes between the PDNO administration.
  • Hemodynamic and ventilation parameters including local blood flow in the target organ and fraction of exhaled nitric oxide (FENO; CLD 77, ECO PHYSICS, Switzerland) were continuously recorded (Acqknowledge Software, BIOPAC® Systems Inc, CA, USA). Arterial blood gas analyses were collected at the end of all doses (GEM5000, Werfen, MA, USA).
  • Left femoral and left carotid blood flow started to increase at 1 nmol kg -1 min -1 and the SMA blood flow at 30 nmol kg -1 min -1 during intraarterial PDNO administration at the respective infusion site (P ⁇ 0.05 compared with baseline, figure 2A and 2B (left carotid), figure 2C and 2D (left femoral), and Figure 3A and 3B (SMA)).
  • the contralateral (i.e. right) artery was unaffected in the femoral experiments but significantly increased at above 30 nmol kg -1 min -1 in the carotid experiments (P ⁇ 0.05, figure 2A).
  • the mean systemic arterial pressure i.e.
  • MAP MAP
  • nmol kg -1 min -1 nmol kg -1 min -1 in the carotid and femoral experiments, respectively
  • P ⁇ 0.05, figure 2B and 2D 3000 nmol kg -1 min -1 in the SMA experiments
  • Corresponding effect on MAP by intravenous administered PDNO was seen at 10 nmol kg -1 min -1 (P>0.05, figure 2B, 2D, 3B and 3D).
  • Cardiac output was unchanged during the experiments except for the last three doses in the carotid experiments (P ⁇ 0.05).
  • End-tidal NO started to increase at 30 nmol kg -1 min -1 in the femoral, carotid and renal experiments (P ⁇ 0.05 compared with baseline) and at 3000 nmol kg -1 min -1 in the SMA experiments (P ⁇ 0.05 compared with baseline, figure 2B, 2D, 3B and 3D).
  • the corresponding increase in the intravenous experiments was in at 10 nmol kg -1 min 1 (P ⁇ 0.05 compared with baseline, figure 2 and 3).
  • the estimated coefficient, and thus the estimated dose-ratio for equivalent effects compared with intravenous infusion, between administration routes using logETNO was 2.7, 2.9, 2.6 and 47 for femoral, carotid, renal and SMA infusion, with intravenous PDNO infusion as a reference (figure 4). These results correspond to those exhibited on the hemodynamics.
  • the methemoblobin fraction was significantly higher in the SMA experiments at the two highest doses compared to baseline (P ⁇ 0.05, figure 5).
  • the other administration routes did not change the methemoglobin fraction, which is also particularly surprising and unexpected.
  • the SaOz decreased significantly at 30 and 100 nmol kg 1 min -1 in the carotid and femoral experiments, respectively (P ⁇ 0.05 compared with baseline).
  • the circulation times between the carotid and femoral intraarterial injection sites to the central intravenous injection site were calculated to 8.5 s and 8.4 s as depicted in Table 1 below.
  • Table 1 Half-life estimation derived from the injection and infusion experiments with PDNO in two anesthetized pigs. Circulation time between the intraarterial and intravenous injection site was also estimated with injection of 10 ml 5% sodium bicarbonate solution. Dose-ratio (DR) was derived from the experiments with intraarterial and intravenous infusions ( Figures 1 to 5).
  • Organ-directed intraarterial (carotid, femoral and superior mesenteric) infusions of PDNO increased organ-specific blood flow dose-dependently in contrast to renal arterial and intravenous infusions.
  • the effective dose needed for increased carotid, superior mesenteric and femoral blood flow had no or minor effects on systemic blood pressure.
  • Methemoglobin levels were lower than 3% during intraarterial organ directed infusion in doses up to 300 nmol kg 1 min -1 .
  • the half-life of PDNO in vivo varied slightly depending on the experimental setup and was estimated to be in the range of 3.0 to 6.1 s.
  • Example 3 Anti-platelet aaareaatorv effects of intravenous PDNO administration
  • Nitric oxide (NO) in exhaled air was measured through the endotracheal tube (Eco physics, Durnten, Switzerland). The animals were covered with heat blankets aiming for normal body temperature. After the experiments the animals received an overdose of propofol followed by 20 mL Potassium chloride (B. Braun Medical Inc. PA, USA) euthanasia was confirmed by ECG and ETCO2.
  • pulmonary embolism was induced by injection of the coagulated blood in the right external jugular vein to a target mean pulmonary arterial pressure of 45-55 mmHg.
  • an intravenous norepinephrine infusion was started and titrated to maintain mean systemic arterial pressure above 60 mmHg.
  • Fraction of inspired oxygen (FiOz) was increased to maintain normal arterial oxygenation and respiratory frequency was increased to adjust for part of the hypercapnia.
  • an intravenous infusion of PDNO at 160 nmol kg -1 min -1 was started and continued for approximately 15 min and then it was discontinued.
  • the animals were euthanized with a fast intravenous injection of 40 mM potassium chloride after a bolus dose of 200 mg of propofol. Asystole was confirmed with hemodynamic and respiratory measurements.
  • the primary outcome was change in PAR-1 agonist peptide SFLLRN induced platelet aggregation between the measurement points pulmonary embolization and intravenous PDNO infusion (by a pairwise comparison [Dunn's test] if Friedman test including all four time points found a P-value ⁇ 0.05). Secondary outcomes were change in hemodynamic variables, end-tidal NO and blood gas values comparing pulmonary embolization with and without PDNO infusion. No statistical analyses were done on secondary outcomes.
  • Pulmonary embolization induced acute pulmonary hypertension with systemic hypotension (which was reversed with norepinephrine infusion), arterial deoxygenation (which was reversed by increasing FiOz), hypercapnia (which was partly reversed by increasing respiratory frequency) and increased end-tidal NO.
  • Intravenous PDNO infusion caused decreased pulmonary and systemic vascular resistance as well as increased end-tidal NO; effects that were reversed when stopping the PDNO infusion.
  • thrombin mimetic hexapeptide SFLLRN This peptide is an agonist towards the main thrombin receptor designated protease-activated receptor-1 (PAR-1). Inhibitory effects of PDNO were elucidated in isolated suspensions of human platelets and in whole blood.
  • Heparinized human or pig blood (0.5 ml) was diluted 1 : 1 with Krebs-Ringer glucose (KRG) buffer (isotone saline, pH 7.4). The diluted blood was transferred into analyse cuvettes and placed in a Multiplate aggregometer. Platelet aggregation in vitro (human blood) and ex vivo (pig blood) was measured as increase in electrical impedance between two platinum electrodes. Measurements were conducted at 37°C under stirring conditions.
  • KRG Krebs-Ringer glucose
  • PDNO or nitroglycerine used as control drug was introduced 2 min prior to the hexapeptide SFLLRN.
  • This hexapeptide acts as agonist to the main thrombin receptor designated protease-activated receptor-1 (PAR-1).
  • PAR-1 protease-activated receptor-1
  • PDNO was given intravenously to anaesthetized pigs. After blood drawing, diluted blood was transferred to the Multiplate instrument and stimulated by SFFLRN. Aggregation responses were registered during 10 min and expressed as area under curve.
  • Platelet aggregation in whole blood was analysed as increases in electrical resistance (impedance changes between two platinum electrodes) using a Multiplate aggregometer.
  • Heparinized blood was obtained from healthy volunteers and immediately mixed with an acid citrate dextrose (ACD) solution at a volumetric proposition of 5 parts blood and 1 part of ACD.
  • ACD acid citrate dextrose
  • the platelets were centrifuged for 20 min at 220xg to obtain platelet-rich plasma. Thereafter, platelets were pelleted by a second centrifugation (20 min at 480xg) and gently resuspended in KRG buffer.
  • 0.3 ml of isolated platelet suspension (2.5x108 platelets/ml) was placed in a Chrono-log aggregometer and analyses were conducted at 37 degrees under stirring conditions. Platelets were stimulated with PDNO or nitroglycerine for 2 min and thereafter activated by SFLLRN. Platelet aggregation was assessed as % increase in light transmission through the cuvettes (light transmission in platelet-free KRG represent 100%).
  • Fig 8 shows that PDNO, but not nitroglycerine significantly inhibited SFLLRN-induced platelet aggregation under these experimental conditions. This finding indicates that PDNO produces antithrombotic actions even in whole blood and in the presence of haemoglobin.
  • VASP vasodilator-stimulated phosphoprotein
  • VASP vasodilator-stimulated phosphoproteins
  • Example 5 Intraarterial infusion of PDNO to treat acute lower limb embolisation
  • a 5 Fr catheter (Soft-Vu Berenstein, USA) was inserted through the brachial artery via a 5 Fr (Cordis Corportation, USA) introducer and advanced to the common femoral artery (CFA). Positions confirmed by fluoroscopy.
  • a flow probe (Transonic Systems Inc. NY, USA) was placed on the CFA bilaterally, 3 mm on the left side, 6 mm on the right side.
  • a laser doppler probe Perimed, Sweden was placed in the peroneus muscles of the hind limb and a microdialysis catheter (M Dialysis AB, Sweden) was placed in the anterior tibial muscle.
  • Nitric oxide in exhaled air was measured through the endotracheal tube (Eco physics, Durnten, Switzerland). The animals were covered with heat blankets aiming for normal body temperature. After the experiments the animals received an overdose of propofol followed by 20 mL Potassium chloride (B. Braun Medical Inc. PA, USA) euthanasia was confirmed by ECG and ETCO2.
  • the left common femoral artery was selectively embolized through the 5 Fr catheter (Berenstein, USA) with autologous blood clots 1 ml kg -1 (clotting time at a minimum of 2 hours) 5 ml min -1 .
  • embolization block randomization to either treatment with PDNO 3 nmol kg -1 min -1 or control group (no infusion) was performed (figure 10).
  • the NO donor was administered through syringe pumps with a carrier solution (bicarbonate 1,4%) through a microcatheter (Terumo Progreat®, 2.7 Fr.
  • Hemodynamic and ventilation parameters including local blood flow in the CFA was continuously recorded (Acqknowledge Software, BIOPAC® Systems Inc, CA, USA). Laser doppler signal, fraction of exhaled nitric oxide (FENO, apparaten), arterial and local venous blood samples and blood gases and were collected according to protocol (figure 10).
  • FENO fraction of exhaled nitric oxide
  • Femoral venous resistance Femoral arterial blood flow / MAP.
  • Lactate Central arterial lactate level - femoral venous lactate level. Lactate production: Femoral arterial blood flow x A Lactate x -1.
  • Femoral venous O2 consumption (arterial content of O2- femoral venous content of O2) x (arterial femoral blood flow / 1000).
  • Normal distribution was analyzed with Shapiro-Wilk test. Normally distributed data were analyzed using linear mixed model, with group and time as main factors and their interaction followed by multiple interactions. Normal distributed data are presented with mean ⁇ standard error of the mean. Data deviating from normal distribution were analyzed using Mann Whitney U test and presented as median (IQR 25th - 75% percentile). All statistics were performed in SPSS (version 27, IBM Corp., Armonk, NY, USA) and graphs were generated in GraphPad Prism 9.4.1 (GraphPad Software, Inc., San Diego, CA, USA).
  • the PDNO group and the control group were similar at baseline except for cardiac output (CO) and femoral venous oxygen consumption (FV O2) that were higher in the control group at baseline.
  • CO cardiac output
  • FV O2 femoral venous oxygen consumption
  • Blood flow in the common femoral artery (CFA) was extinguished 15 minutes after embolisation in both groups and significantly higher in the PDNO group after start of infusion (figure 11).
  • FVR femoral venous resistance
  • Heart rate, CO and MAP were similar between the groups.
  • Femoral venous (FV) pO 2 , FV VO2 and FV lactate production were all higher in the PDNO group compared to the control group, although not significant (figure 11).
  • Femoral venous CO2 level was significant higher in the control group at three hours of infusion and FV O2 levels were generally higher in the PDNO group although not significant.
  • ETNO and MHb levels were higher, and pO 2 generally lower, in the PDNO group although not significant (figure 12).

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Abstract

La présente invention concerne des méthodes de traitement d'une affection, un tel traitement comprenant l'administration de certains propanediols mono- et/ou bis-nitrosylés, y compris des compositions et des formulations associées, et ladite administration se faisant à un patient en ayant besoin par perfusion intra-artérielle à une dose d'environ 0,01 à 3000 nmol kg-1min-1. La présente invention concerne également l'utilisation de propanediols mono- et/ou bis-nitrosylés pour le traitement d'une maladie thromboembolique.
PCT/EP2024/061806 2023-04-27 2024-04-29 Propanediols mono- et bis-nitrosylés destinés à être utilisés dans le traitement d'une maladie thromboembolique Pending WO2024223950A1 (fr)

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