EA039635B1 - Treatment or prevention of cardiovascular events using a colchicine derivative - Google Patents

Abstract

The invention relates to the field of medicine. Provided is a method for the treatment and/or prevention of a cardiovascular event in a subject in need thereof, comprising administering 0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof or any combination thereof to the subject once per day, wherein the cardiovascular event is one or more of acute coronary syndrome, out-of-hospital cardiac arrest or noncardioembolic ischemic stroke, and wherein colchicine or a pharmaceutically acceptable salt thereof or any combination thereof is comprised in a composition which is one tablet or liquid composition. Also provided is a method for reducing long-term risks of atherosclerotic vascular disease in a subject in need thereof, comprising administering to the subject 0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof or any combination thereof to the subject once per day, wherein the subject is diagnosed with clinically stable atherosclerotic vascular disease. The methods of the invention provide the successful treatment and prevention of cardiovascular events and other etiologically related diseases using lower doses of colchicine than used before.

Description

BACKGROUND OF THE INVENTION

The following description of the background of the present invention is only intended to facilitate understanding of the present invention. The description is not an endorsement or admission that any material referred to is or was part of the prior art at the time of the priority date of the application for this invention.

In patients diagnosed with atherosclerotic vascular disease, the affected vessel wall undergoes a destructive action that promotes the formation of plaque on the vessel wall and its instability, which can cause coronary artery occlusion leading to heart attack, ischemic stroke and sudden death.

The response to damage in the affected vessel depends on the structure and content of atherosclerotic plaques. Lipid-rich plaques with a neovascular backbone are primarily damaged, and as a result are infiltrated by neutrophils. Neutrophils that infiltrate the interior can become activated upon contact with plaque contents, which initiates an aggressive inflammatory response that can accelerate plaque instability, increasing the risk of plaque growth and rupture and therefore increasing the risk of clinical events.

Despite standard treatment with antithrombotic drugs and statins, patients diagnosed with atherosclerotic vascular disease remain at risk of developing cardiovascular events, possibly due to the fact that these treatments do not target some of the inflammatory pathways involved in the development of the disease.

There are a number of additional ways to prevent or reduce the risk of developing coronary heart disease, including treatment with the following drugs: antithrombotic agents (except aspirin), anticoagulants, angiotensin-converting enzyme inhibitors (ACE inhibitors), aldosterone antagonists (AARs), β-blockers, calcium channel blockers and/or nitrates.

However, many of these therapies are recommended for the treatment of acute conditions and are not directed or intended for the long-term reduction of the severity of cardiovascular events in patients diagnosed with clinically stable atherosclerotic vascular disease.

In connection with the above, the present invention is proposed.

The purpose of the present invention is to eliminate, or at least partially eliminate, one or more of the disadvantages of the prior art mentioned above, or to provide the consumer with an acceptable or commercial choice.

Brief description of the essence of the invention

The present invention provides a method for treating and/or preventing a cardiovascular event in a subject in need thereof, comprising administering 0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof, or any combination thereof, to the subject once a day where the cardiovascular event is one or more of acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke, and wherein colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is contained in a single tablet or liquid formulation.

Preferably, the method further comprises co-administering to the subject a second agent for treating and/or preventing a cardiovascular event in the subject, wherein the second agent is a statin; where the statin is one or more of atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin and pravastatin.

Preferably, the method further comprises co-administering to the subject a second agent for treating and/or preventing a cardiovascular event in the subject, wherein the second agent is an antithrombotic agent; wherein the antithrombotic agent is one or more of an irreversible cyclooxygenase inhibitor, an adenosine diphosphate (ADP) receptor inhibitor, a phosphodiesterase inhibitor, an IIB/IIIA glycoprotein inhibitor, an adenosine reuptake inhibitor, a thromboxane inhibitor, and a thromboxane receptor antagonist.

Preferably, the subject is co-administered with a second agent for the treatment and/or prevention of atherosclerotic vascular disease, wherein the second agent is a statin or an antithrombotic agent; where the statin is one or more of atorvastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin, pitavastatin and pravastatin and where the antithrombotic agent is one or more of an irreversible cyclooxygenase inhibitor, an adenosine diphosphate (ADP) receptor inhibitor, a phosphodiesterase inhibitor, a glycoprotein IIB/IIIA inhibitor , an adenosine reuptake inhibitor, a thromboxane inhibitor, and a thromboxane receptor antagonist.

Preferably, the subject has or has been diagnosed with atherosclerotic vascular disease. Preferably the subject is a human.

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The present invention also provides a method for reducing the long-term risks associated with atherosclerotic vascular disease in a subject in need thereof, comprising administering

0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof, or any combination thereof, to a subject once daily where the subject has been diagnosed with clinically stable atherosclerotic vascular disease.

Preferably the subject is a human. Preferably, colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is administered for at least 24 months. Preferably, the subject also has stable coronary heart disease and/or cholesterol crystal-induced inflammation of atherosclerotic plaques. Preferably, said stable coronary heart disease is clinically stable coronary heart disease. Preferably, colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is contained in a composition wherein the composition is administered in the form of a tablet, capsule, liquid composition, gel, or once daily powder form. Preferably the composition is liquid. Preferably, colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is contained in a composition, wherein the composition further comprises a therapeutically effective amount of a statin and an antithrombotic agent.

Brief description of the figures

In FIG. 1 is a diagram of the process for selecting subjects to participate in the clinical trial described in Example 1.

In FIG. 2 is a graph showing the time to the first clinical event in each treatment group.

In FIG. 3 is a table showing the time to the registration of the first clinical event in the studied subgroups.

In FIG. 4 is a graph showing the time to the first clinical event in each treatment group, grouped by specific events.

Detailed description of the invention

Main content.

Those skilled in the art will appreciate that variations and modifications of the present invention are possible other than those detailed herein. The present invention includes all such variations and modifications. The present invention also includes all steps, features, compositions and compounds referred to in the description or specified in the description, individually or in the aggregate, as well as any and all possible combinations or any two or more steps or features.

Each document, reference, patent application or patent cited in this context is expressly incorporated herein by reference in its entirety, i.e. indicates that the cited document is to be considered as part of the present specification. Re-citation of a document, reference, patent application or patent is excluded for the sake of brevity. Any manufacturer's instructions, descriptions, product specifications, and flow charts for any products mentioned in this context or in any document incorporated herein by reference are hereby incorporated by reference herein and may be used in the practice of this inventions in practice. It is not assumed that any of the references relate to the prior art or is part of the prior art in the field to which the present invention pertains.

The scope of the present invention is not limited to any specific embodiments described in this context. These options are given only as examples. Functionally equivalent products, compositions and methods are apparent within the scope of the present invention, which is defined in this context.

The invention described in this context may include one or more ranges of values (eg, size, deviation, and signal strength, etc.). It should be understood that a range of values includes all values within the specified range, including values that define the limits of the range, as well as values adjacent to the limits of the range, which lead to the same or substantially the same result, as well as values immediately adjacent to the value, defining the boundary of the range.

In the detailed description of the present invention, other definitions are given for selected terms used in this context, and they can be used in the present description. Unless otherwise indicated, all other scientific and technical terms used in this context have the generally accepted meanings known to a person skilled in the art to which the present invention pertains. The term active agent may refer to one active agent or include two or more active agents.

As used herein, unless the context requires otherwise, the word contain, or variants such as contains or containing, should be understood to mean the inclusion of the specified integer or group of integers without excluding any other integer or group of integers.

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Detailed description

It is widely known that the use of a number of non-steroidal anti-inflammatory agents, such as Vioxx® (rofecoxib), Celebrex® (celecoxib), ibuprofen, Voltaren® (diclofenac), in patients who have previously been diagnosed with coronary heart disease or other atherosclerotic vascular disease, may lead to a significant increase in the risk of other cardiovascular events, such as myocardial infarction. Other anti-inflammatory agents, such as cortisone, may also increase the risk of side effects and cardiovascular events in patients with pre-existing coronary heart disease. Despite the anti-inflammatory actions of these agents and their ability to reduce levels of inflammatory markers (eg, lowering C-reactive protein levels), they are contraindicated in the treatment of patients diagnosed with coronary heart disease or other atherosclerotic vascular disease.

In atherosclerotic vascular disease, the walls of the arteries thicken as a result of the accumulation of calcium and fatty compounds such as cholesterol. Syndrome that affects the arterial blood vessels is a chronic inflammatory response in the walls of the arteries, primarily due to atheromatous plaques. Plaque destruction can cause acute coronary syndrome (including ischemic chest pain, acute myocardial infarction, unstable angina), cardiac arrest and/or stroke, such as non-cardioembolic ischemic stroke.

Coronary disease and coronary heart disease are a form of atherosclerotic vascular disease caused by a buildup of plaque along the inner walls of the arteries of the heart, which narrows the artery and reduces blood flow to the heart. Stable coronary disease refers to diseases whose intensity, nature or frequency is predictable under known levels of physical exertion or other stimuli. Unstable coronary diseases include diseases whose intensity, nature or frequency change.

The present invention has surprisingly found that administration of an anti-inflammatory agent along with colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof, can have a curative or prophylactic effect on cardiovascular events in patients diagnosed with atherosclerotic vascular disease, such as coronary heart disease.

Colchicine and its derivatives, as well as methods for their preparation, are described in the following publications, the contents of which are incorporated herein by reference:

Kouroupis R., Hansen H.-J., From Colchicine and Some of Its Derivatives to

1,2,3,9,10-Pentamethoxybenzo[a]heptalenes, Helvetica Chimica Acta, t. 78, pp. 1247-1277(1995),

Sun L., McPhail A.T., Hamel E., Lin C.M., Hastie S.B. et al., Antitumor Agents, 139, Synthesis and Biological Evaluation of Thiocolchicine Analogs 5,6-Dihydro-6(S)-(acyloxy)- and 5,6-Dihydro-6(S)-(aroyloxy)methyl-l, 2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthale n-8-ones as Novel Cytotoxic and Antimitotic Agents, Journal of Medicinal Chemistry, t. 36(5), pp. 544-551 (1993),

Kouroupis P., Kessler J., Hansen H.-J., 10-Alkyl-10-demethylcolchicines, Helvetica

Chimica Acta, t. 79, pp. 208-212 (1996),

Chang D.-J., Jung J.-W., An H., Suh Y.-G., Yoon E.-Y., Lee G-B., Kim S.-O., Kim W-J. , Kim Y.-M., Design, synthesis and identification of novel colchicine-derived immunosuppressant, Bioorganic and Medicinal Chemistry Letters, t. 19 (15), pp. 4416-4420 (2009),

Kozaka T., Nakagawa-Goto K., Shi Q., Lai C.-Y., Brossi A., Lee K.-H., Hamel E., Bastow

K.F., Antitumor agents, 273, Design and synthesis of N-alkyl-thiocolchicinoids as potential

- 3 039635 antitumor agents, Bioorganic and Medicinal Chemistry Letters, t. 20 (14), cc 4091-4094 (2010),

Danieli B., Giardini A., Lesma G., Passarella D., Peretto B., Sacchetti A., Silvani A., Pratesi G., Zunino F., Thiocolchicine-Podophyllotoxin Conjugates: Dynamic Libraries Based on Disulfide Exchange Reaction, Journal of Organic Chemistry, t. 71, 7, pp. 2848-2853 (2006),

Quinn F.R., Neiman Z., Beisler J.A., Toxicity Quantitative Structure-Activity Relationships of Colchicines, Journal of Medicinal Chemistry, t. 24(5), pp. 636-639 (1981),

Bensel N., Lagnoux D., Niggli V., Wartmann M., Reymond J.-L., New C(4)-Functionalized Colchicine Derivatives by a Versatile Multicomponent Electrophilic Aromatic Substitution, Helvetica Chimica Acta, t. 87(9), pp. 2266-2272 (2004),

Malysheva Yu.B., Fedorov A.Yu., Combes S., Allegro D., Peyrot V., Knochel P., Gavryushin A.E., Synthesis and biological evaluation of novel anticancer bivalent colchicine-tubulizine hybrids, Bioorganic and Medicinal Chemistry, t . 20(14), pp. 4271-4278 (2012),

Kouroupis P., Linden A., Hansen H.-J., Synthesis of 4-Acetylcolchicine, Helvetica Chimica Acta, Vol. 79, pp. 203-207 (1996),

Bensel N., Lagnoux D., Niggli V., Wartmann M., Reymond J.-L., New C(4)-Functionalized Colchicine Derivatives by a Versatile Multicomponent Electrophilic Aromatic Substitution, Helvetica Chimica Acta, t. 87(9), pp. 2266-2272 (2004),

Chang D.-J., Jung J.-W., An H., Suh Y.-G., Yoon E.-Y., Lee G-B., Kim S.-O., Kim W.-L , Kim Y.-M., Design, synthesis and identification of novel colchicine-derived immunosuppressant, Bioorganic and Medicinal Chemistry Letters, t. 19, no. 15, pp. 4416-4420 (2009),

Hufford CD, Capraro H.-G., Brossi A., ⁽¹³⁾ C- and ^(I) HNMR. Assignments for Colchicine Derivatives, Helvetica Chimica Acta, t. 63(1), pp. 50-56 (1980)

Nicolaou K.C., Valiulin R.A., Pokorski J.K., Chang V., Chen J.S., Bio-inspired synthesis and biological evaluation of a colchicine-related compound library, Bioorganic and Medicinal Chemistry Letters, t. 22, no. 11, pp. 3776-3780 (2012),

Patil S.A., Wang J., Li X.S., Chen J., Hosni-Ahmed A., Patil R., Li W., Miller D.D., Jones T.S., Seibel W.L., New substituted 4H-chromenes as anticancer agents, Bioorganic and Medicinal Chemistry Letters, t. 22, no. 13, pp. 4458-446 (2012),

Nielsen K., Manchanda R., Deuterium-enriched colchicines, Thiocolchicine and derivatives thereof, Methods of preparation and use thereof, Patent: US 2011/178180 Al (2011),

BartusikD., TomanekB., Fallone G., LattovaE., Perreault H., Tuszynski J., Derivatives of thiocolchicine and its applications to CEM cells treatment using ¹⁹ F Magnetic Resonance ex vivo Bioorganic Chemistry, t. 38, no. 1, pp. 1-6 (2010),

Alali F.Q., Qandil A., Gharaibeh A.A., Ghawanmeh A., Tawaha K., Burgess J.P., Sy A.,

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Nakanishi Yu., Kroll D.J., Oberlies N.H., Colchicinoids from Colchicum crocifolium Boiss, Colchicaceae, Natural Product Research, t. 24(2), pp. 152-159 (2010),

Boyer F.-D., Dubois J., Thoret S., Dau M.-E.T.H., Hanna I., Synthesis and tubulin-binding properties of new allocolchicinoids, Bioorganic Chemistry, t. 38(4), pp. 149-158 (2010),

Yang B., Zhu Z.C., Goodson H.V., Miller M.J., Syntheses and biological evaluation of ring-C modified colchicine analogs, Bioorganic and Medicinal Chemistry Letters, t. 20(12), pp. 3831-3833 (2010),

Stefely J.A., Miller P.A., Peterson R.J., Moraski G.C., Miller M.J., Palchaudhuri R., Hergenrother P.J., N-((l-benzyl-lH-l,2,3-triazol-4-yOmethyOarylamide as a new scaffold that provides rapid access to antimicrotubule agents: synthesis and evaluation of antiproliferative activity against select cancer cell lines, Journal of Medicinal Chemistry, t.53 (8), pp. 3389-3395 (2010),

Kozaka T., Nakagawa-Goto K., Shi Q., Lai C.-Y., Brossi A., Lee K.-H., Hamel E., Bastow K.F., Antitumor agents, 273, Design and synthesis of N- alkyl-thiocolchicinoids as potential antitumor agents, Bioorganic and Medicinal Chemistry Letters, t. 20(14), pp. 4091-4094 (2010),

Johansson E.M.V., Darbre T., Reymond J.-L., Dubois J., Glycopeptide dendrimer colchicine conjugates targeting cancer cells, Bioorganic and Medicinal Chemistry, t. 18(17), pp. 6589-6597(2010),

Dietrich A., Mueller T., Schobert R., Biersack B., Effenberger K., Knauer S., 4-(3-Halo/amino-4,5-dimethoxyphenyI)-5-atyloxazoles and-N-methylimidazoles that are cytotoxic against combretastatin a resistant tumor cells and vascular disrupting in a cisplatin resistant germ cell tumor model, Journal of Medicinal Chemistry, t. 53 10(18), pp. 6595-6602(2010),

Nicolaus N., Neudoerfl J.-M., Schmalz H.-G., Zapke J., Oschkinat H., Riesterer P., Prokop A., Azides derived from colchicine and their use in library synthesis: A practical entry to new bioactive derivatives of an old natural drug, Chern. Med. Chern., t. 5(5), pp. 661-665 (2010),

Sharma S., RavindraR., Blanden A.R., Bane S., Poliks B., Chiauzzi C, Characterization of the colchicine binding site on avian tubulin isotype 131/1, Biochemistry, t. 49(13), pp. 2932-2942 (2010),

Indena S.P.A., Process for the glycosidation of colchicine and thiocolchicine, Patent: EP2128170 Al (2009),

Sun T., Nielsen K., Watson S., Hilfiker R., Sieber A., Colchicine Solid-State forms: Methods of Making and Methods of Use Thereof, Patent: US 2009/312430 Al (2009),

Bartusik D., Tomanek B., Fallone G., Lattova E., Perreault H., Tuszynski J., The efficacy of new colchicine derivatives and viability of the TLymphoblastoid cells in three-dimensional culture using 19F MRI and HPLCUV ex vivo, Bioorganic Chemistry, t. 37(6), pp. 193-201 (2009),

Chang D.-J., Jung J.-W., An H., Suh Y.-G., Yoon E.-Y., Lee G-B., Kim S.-O., Kim W.-J ., Kim Y.M., Design, synthesis and identification of novel colchicine-derived immunosuppressant, Bioorganic and Medicinal Chemistry Letters, t. 19 (15), pp. 4416-4420 (2009),

ALBERTA HEALTH SERVICES, Novel Colchicine Derivatives, Methods and Uses Thereof, Patent: W0 2011/22805 Al (2011),

MUTUAL PHARMACEUTICAL COMPANY, INC., MANCHANDA, Rajesh, Thiocolchicine Derivatives, method of making and method of use thereof, Patent: W02010/13 8670A2(2010).

Thus, the present invention provides a method for treating and/or preventing a cardiovascular event in a subject in need thereof, comprising administering 0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof, or any combination thereof, to the subject once a day, where the cardiovascular event is one or more of an acute coronary syndrome,

- 5 039635 out-of-hospital cardiac arrest or non-cardioembolic ischemic stroke, and where colchicine, its pharmaceutically acceptable salt, or any combination thereof is contained in a composition that is a single tablet or liquid composition.

The method may include the additional step of co-administering a second agent to treat and/or prevent a cardiovascular event in a subject. For example, the composition delivered by said method may further comprise an antithrombotic treatment agent. Such antithrombotic agents include irreversible cyclooxygenase inhibitors (such as aspirin), adenosine diphosphate receptor (ADP) inhibitors such as clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilinta®), ticlopidine (Ticlid®), cangrelor), phosphodiesterase inhibitors (such as cyclostazol (Pletal®)), glycoprotein IIB/IIIA inhibitors (such as abciximab (ReoPro®), eptifibatide (Integrilin®), tirofiban (Aggrastat®)), adenosine reuptake inhibitors (such as dipyridamole (Persantine®) )), thromboxane inhibitors, including thromboxane synthase inhibitors and thromboxane receptor antagonists (such as terutroban).

In addition, the composition delivered by this method may include one or more statins. Statins that can be used in the composition of the present invention include simvastatin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin and rosuvastatin.

The additional statin and/or antithrombotic agent may be administered simultaneously with colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof, e.g., in the form of tablets or capsules taken simultaneously, taken one after the other for 1 hour, for 2, 4, 6, 8 or 12 hours or during the day. Alternatively, the additional statin and/or antithrombotic agent may be contained in the same dosage form (eg, in a single tablet or capsule) along with colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof.

The present invention also provides a method for reducing the long-term risks associated with atherosclerotic vascular disease in a subject in need thereof, comprising administering 0.5-0.6 mg of colchicine, or a pharmaceutically acceptable salt thereof, or any combination thereof, to the subject once daily, wherein the subject is diagnosed with clinically stable atherosclerotic vascular disease.

The colchicine of the present invention can be used in free base form or in the form of acid addition salts. The acid addition salts are preferably pharmaceutically acceptable non-toxic addition salts of suitable acids, such as salts of inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric and phosphoric acids, or organic acids, such as organic carboxylic acids, for example glycolic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicylic, orthoacetoxybenzoic, nicotinic or isonicotinic acid, or organic sulfonic acids such as methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, toluene-parasulfonic or naphthalene-2-sulfonic acids.

Without reference to any theory, it is believed that the activity of colchicine and/or its salt in preventing the development of cardiovascular events in patients diagnosed with coronary heart disease may be due to the suppression of neutrophil function, leading to a decrease in the risk of plaque instability and, thus Thus, the risk of developing de novo cardiovascular events due to the destruction of native atherosclerotic plaques in patients diagnosed with atherosclerotic vascular disease, such as coronary heart disease. For example, colchicine can prevent the activation and amplification of cholesterol crystal-induced inflammation of atherosclerotic plaques, and therefore act to slow the progression of atherosclerosis, as well as contribute to the stabilization of atherosclerotic plaques.

The present invention provides a method for treating and/or preventing a cardiovascular event in a subject in need thereof, comprising administering 0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof, or any combination thereof, to the subject once a day where the cardiovascular event is one or more of acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke, and wherein colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is contained in a single tablet or liquid formulation.

The method of treatment and/or prevention of the present invention provides for the treatment or prevention of one or more of the following cardiovascular events: acute coronary syndrome (including ischemic chest pain, acute myocardial infarction, unstable angina), out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke.

As a rule, the terms treat and treatment, as well as their derivatives, used in this context, denote the action on a subject, tissue or cell in order to achieve the desired pharmacological and/or physiological effect. The treatment may be therapeutic in terms of preventing the progression of coronary heart disease or other atherosclerotic vascular disease, as well as cardiovascular events, or resulting in partial or complete recovery and/or regression of coronary heart disease or other atherosclerotic vascular disease, as well as cardiovascular events.

The terms prevention or prophylaxis, as well as their respective derivative terms, refer to the partial or complete prevention, or at least slowing the onset of coronary heart disease or other atherosclerotic vascular disease and cardiovascular events, or the development of related symptoms in a subject who has not previously been diagnosed with a diagnosis of coronary heart disease or other atherosclerotic vascular disease, or no previous history of a cardiovascular event that has been diagnosed with coronary heart disease and may be in remission, and recurrence of the coronary heart disease and/or cardiovascular event must be prevented, or that was included in the risk group for the development of coronary heart disease or other atherosclerotic vascular disease, and in which a cardiovascular event was observed.

The precise amount of colchicine and/or salt thereof will depend upon the mode of delivery, the nature of the coronary heart disease or other atherosclerotic vascular disease, the therapeutically effective amount of colchicine required, and the general health of the subject to whom the composition is administered.

Preferably the concentration of colchicine and/or its salt is high enough (quantum satis) to provide a therapeutically effective dose in target cells. Such therapy may be directed to the treatment or prevention of a cardiovascular event in a subject. More preferably, the therapeutically effective dose is for the treatment or prevention of a cardiovascular event in a subject diagnosed with atherosclerotic vascular disease, such as stable or unstable coronary heart disease.

Compositions of the present invention comprising colchicine and/or a salt thereof are preferably optimized for delivery to a subject in need of treatment more than once a day, once a day, or less frequently. For example, if the composition is optimized for oral delivery, the composition is preferably administered once daily. However, it is contemplated that the composition may be administered more frequently (eg, two or three times a day) or less frequently (eg, every other day, every other day, once a week). Alternatively, if the composition comprising colchicine and/or a salt thereof is in the form of an injectable formulation, the composition is preferably optimized for weekly or monthly delivery.

The compositions may further include one or more additional agents selected from a list including a statin and/or an antithrombotic agent.

As used herein, the term "therapeutically effective amount" refers to an amount of colchicine and/or a salt thereof that is effective to provide the desired therapeutic response, eg, to prevent or treat a cardiovascular event in a subject. The specific therapeutically effective amount will vary depending on such factors as the particular condition being treated and the medical history of the subject, the species of animal in need of treatment, the duration of treatment, the course of concomitant treatment (if any), the specific formulations used, and the structure of the composition.

As used herein, the terms pharmaceutically, physiologically or veterinarily acceptable refer to pharmaceutically active agents, physiologically active agents, veterinary active agents, or inert ingredients that are suitable for use in oral formulations or formulations intended to come into contact with the skin of animals, including humans, without causing toxicity. , incompatibility, instability, irritation, allergic response, etc. taking into account an appropriate benefit/risk ratio.

Excipients, excipients, carriers and diluents for use in the compositions of the present invention include, but are not limited to, water, saline, ethanol, dextrose, glycerol, glycerol and polyhydric alcohols, milk protein, vitamins, animal and vegetable oils, polyethylene glycols, lactose, dextrose, sucrose, sorbitol, mannitol and other sugars, starches, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, cellulose and its derivatives such as microcrystalline cellulose and methylcellulose, polyvinylpyrrolidone, aqueous syrup , methyl-, ethyl- and propylhydroxybenzoates, talc, magnesium carbonate, titanium dioxide, magnesium stearate and inorganic oil or combinations of these substances.

The compositions may further include lubricants, dispersion media, buffering agents, wetting agents, emulsifiers and suspending agents, solvents, preservatives, sweeteners or flavoring agents, antifoam agents, polymers, antioxidants, chelating agents, viscosity modulators, tonicity modifying agents, flavoring agents, colorants, perfumes, opacifiers, suspending agents, binders, fillers, plasticizers, absorption accelerators, and mixtures of these substances.

Preservatives include antimicrobial, antibacterial and antifungal agents, antioxidants, chelating agents and inert gases. The specific choice of component that can be included in the composition described in this context, as a rule, depends on the type of drug product.

In preferred embodiments, the composition is formulated to provide rapid delivery and retention of colchicine and/or salt thereof to the site where therapeutic action is to be achieved, while not significantly affecting the efficacy of the compound. In this regard, it should be understood that the composition of a therapeutically effective composition can be processed in various ways depending on the site of treatment and the method of administration of the composition.

There are a number of pharmaceutical composition design reference materials that one of skill in the art can use when developing compositions including colchicine, such as Remington's Pharmaceutical Sciences, 21st Ed., Mack Publishing Company, Easton, PA, USA (2009), complete the contents of which are included in the present description as references.

A composition comprising colchicine and/or a salt thereof may be administered by standard routes, for example, by oral, topical, parenteral, ocular, ophthalmic, intraventricular, intracranial, intraarticular, intravertebral, intracisternal, intraperitoneal, buccal, rectal, vaginal, intranasal, or aerosol routes, and /or in the form of a spray for inhalation or using an implanted reservoir.

In a preferred embodiment, colchicine and/or a salt thereof is administered internally to treat or prevent a cardiovascular event in a subject. For example, colchicine can be administered orally in the form of a tablet, capsule, liquid dose, gel, or powder, administered by injection, for example, into the bloodstream, muscle tissue, or directly into an organ such as the heart, administered by sublingual, buccal, rectal, or intravaginal delivery, or inhalation.

Pharmaceutically acceptable carriers, excipients and excipients which may be used in oral, parenteral, sublingual, buccal, rectal or intravaginal or inhalation formulations include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems such as α-tocopherol-polyethylene glycol 1000-succinate or other similar polymeric matrices or delivery systems such as nanoparticles, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides vegetable saturated fatty acids, water, salts or electrolytes such as protamine sulfate, disodium phosphate, dipotassium phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based compounds, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, block copolymers of ethylene and oxypropylene, and lanolin.

The composition of the present invention, comprising colchicine and/or its salt, may additionally contain one or more excipients, provided that these substances do not adversely affect the therapeutic effect provided by colchicine and/or its salt. In one embodiment, the excipient is a dye. In other embodiments, the adjuvant is a preservative such as a mold inhibitor or an antioxidant, perfume or stabilizer. Additional excipients can also be agents that convert the composition into an emulsion, microemulsion or nanoemulsion.

In a preferred embodiment, colchicine and/or a salt thereof is administered orally. In this regard, colchicine can be processed into the form of a tablet, capsule, gel or liquid composition. If colchicine and/or a salt thereof is in the form of a tablet, the tablet may additionally contain excipients such as lactose (milk sugar), microcrystalline cellulose, corn starch, sugars (including sucrose, mannitol, sorbitol, fructose and dextrose), whey and yeast, and/or binders such as povidone, xanthan gum and carbopol (Carbopol). Additional ingredients may be disintegrating agents such as crospovidone, croscarmellose sodium and gellan gum, coatings such as shellac, lubricants such as magnesium stearate, stearic acid, sodium stearyl fumarate and hydrogenated vegetable oil, colorants such as titanium dioxide and iron oxides, flavors (in chewable tablets) and plasticizers. Most preferably, colchicine and/or a salt thereof is administered in the form of a tablet comprising colchicine, magnesium stearate, lactose, corn starch and povidone. The tablet, capsule, gel or liquid composition contains 0.5 to 0.6 mg of colchicine and/or a salt thereof, preferably 0.5 or 0.6 mg.

Alternatively, colchicine and/or a salt thereof may be administered by the sublingual, buccal, rectal, or intravaginal route, eg, administered as a tablet, capsule, gel, powder, or spray.

In another embodiment, colchicine and/or a salt thereof is administered parenterally, preferably by injection, eg subcutaneously or intramuscularly. However, for the treatment or prevention of a cardiovascular event in a subject, administration can also be by artery or intraperitoneally. The composition may be in the form of a sterile injectable preparation, for example as a sterile injectable suspension, for the treatment or prevention of a cardiovascular event in a subject. Such a suspension can be processed according to known technology in this field using

- 8 039635 I eat suitable dispersing agents, surfactants and suspending agents (for example, Tween 80). The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (eg, 1,2 propanediol). Suitable carriers and solvents include mannitol, water, Ringer's solution and isotonic buffered sodium chloride solution. In addition, sterile fixed oils can be used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives as well as natural pharmaceutically acceptable oils such as polyoxyethylated olive oil or castor oil can also be used in injectable preparations. The composition for injection contains 0.5 to 0.6 mg of colchicine and/or a salt thereof, preferably 0.5 or 0.6 mg.

The composition may further include a second agent for treating and/or preventing a cardiovascular event in a subject. For example, the composition may further include an antithrombotic treatment agent. Such antithrombotic agents include irreversible cyclooxygenase inhibitors (such as aspirin), adenosine diphosphate receptor (ADP) inhibitors such as clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilinta®), ticlopidine (Ticlid®), cangrelor), phosphodiesterase inhibitors (such as cyclostazol (Pletal®)), glycoprotein IIB/IIIA inhibitors (such as abciximab (ReoPro®), eptifibatide (Integrilin®), tirofiban (Aggrastat®)), adenosine reuptake inhibitors (such as dipyridamole (Persantinef®) )), thromboxane inhibitors, including thromboxane synthase inhibitors and thromboxane receptor antagonists (such as terutroban).

In addition, the composition may include one or more statins. Statins that can be used in the composition of the present invention include simvastatin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin and rosuvastatin.

Examples

The following examples are provided to further illustrate certain embodiments of the present invention.

Example 1

A prospective, randomized, masked evaluation study (PROBE) was conducted to determine the possibility of reducing the risk of developing cardiovascular events in patients with objectively diagnosed clinically stable coronary heart disease with the introduction of 0.5 mg / day of colchicine in combination with a standard secondary prophylactic course of treatment, including use of aspirin and high doses of statins.

Methods.

Conducting and designing clinical trials. A low dose colchicine (LoDoCo) trial was conducted with the assistance of the Heart Research Institute of Western Australia. The trial design was developed by lead investigators registered with the Australian Clinical Trial Registry (12610000293066) and approved by the Human Research Ethics Committee at Sir Charles Gairdner Hospital, Perth in Perth Western Australia in July 2008. The study was conducted without external funding.

A prospective, randomized, open-label study with masked evaluation criteria (PROBE [8]) was used. Patients with a diagnosis of coronary heart disease submitted for standard clinical data review were randomized to colchicine (0.5 mg/day) and no colchicine, with no other change in patient medication. All results were evaluated by a qualified researcher not familiar with the distribution of groups.

Sample size and selection criteria. A study population was planned to include 250 patients randomized to the control group and 250 patients randomized to the treatment group who were well tolerated to colchicine for at least 4 weeks from the date of their randomization.

The study included patients meeting each of the following criteria: 1) angiographically proven coronary heart disease, 2) age 35 to 85 years, 3) clinical stability for at least 6 months, 4) absence of major alternative comorbidities or contraindications to treatment with colchicine, 5) informed consent to the course of treatment with visits to the doctor for standard cardiac follow-up examinations, and 6) informed consent with participation in the study and with randomization to groups. Patients who had previously undergone coronary bypass surgery were included in the study only if coronary bypass surgery was performed more than 10 years ago, or they had graft rejection based on angiographic data, or stenting was performed due to coronary bypass 9 039635 . All patients signed an informed consent prior to randomization.

Randomization. The randomization sequence was computer generated, throughout the study the sequence was closed to investigators, and the sequence was administered by an investigator assistant who was not involved in the evaluation or control of study patients. After informed consent was obtained by the assistant, patient demographics were entered into a database, and investigators and patients were encouraged to record the treatment group in which the patient was included.

Despite the selection of the lowest dose of colchicine available, it was expected that a number of patients would discontinue treatment immediately after randomization due to gastrointestinal side effects. In order to ensure the required number of patients in the treatment group who tolerated treatment well, if the patient stopped taking colchicine during the first month due to side effects, the investigator's assistant could, according to the protocol, enroll a new selected patient in the study. Patients who did not tolerate treatment were not excluded from the studies and were examined in the usual way, while patients were included in the primary statistical analysis of all randomized patients.

Experimental study. Patients randomized to the active treatment group received 0.5 mg colchicine per day from the attending cardiologist. The drug was dispensed by a staff pharmacist and, if necessary, patients paid for the cost of said drug. All other courses of treatment continued in the standard manner.

Examination and evaluation of clinical results. Patients' compliance with treatment and clinical outcome data were collected at physician follow-up visits, as well as at any unscheduled hospital visit.

Acute coronary syndrome (ACS) was defined as the following: (a) acute myocardial infarction (AMI), evidenced by acute ischemic chest pain accompanied by an increase in serum troponin above the upper limit of normal [9], or (b) unstable angina pectoris (NS), the evidence of which was a recent exacerbation of angina pectoris in patients, not associated with an increase in serum troponin levels, but associated with a change in the patient's coronary structure according to angiographic data. (Classification of unstable angina according to Braunwald (Braunwald) classes IB and IIB) [10]. ACS was characterized as stent-related disease if there was evidence of significant narrowing within the stent or acute stent thrombosis.

Community-acquired cardiac arrest was defined as sudden death as evidenced by the patient's death certificate, or non-fatal community-acquired cardiac arrest, defined as recovery from sudden collapse (acute vascular insufficiency) associated with documented asystole, ventricular tachycardia, or ventricular fibrillation.

Non-cardioembolic ischemic stroke was defined as an ischemic stroke confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) that was determined by the treating neurologist to be not due to atrial fibrillation or intracranial hemorrhage.

The primary clinical outcomes were a combination condition, ACS, fatal or non-fatal out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke.

Secondary clinical outcomes were (a) individual components of primary clinical outcomes and (b) components of ACS unrelated to stent-related disease.

Chronological sequence. The predetermined duration of the study was a minimum of two years for all patients. Accordingly, the study was terminated on May 31, 2012. During May, all surviving patients were contacted by telephone and consented to treatment, while investigators collected clinical outcome data up to the last date of the study. Final clinical results were obtained for all patients, and all patients were examined.

Statistical power of research. Whereas in the control group, 8% (11) of patients had a combined event rate (ACS, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke), a 2-year ramp-up period, and follow-up after a 2-year ramp-up period , the planned sample size provided >80% statistical power to determine a hazard ratio <0.50 based on a 5% two-tailed significance level.

Data analysis. Summary statistics, including mean and standard deviation, were calculated for all baseline characteristics for patients in the treatment group. During the entire time period leading up to the clinical outcome of an event, clinical outcomes were calculated by day by subtracting the date of randomization from (1) the date of the event or death or (2) the date of completion of the trial for

- 10 039635 patients in whom the studied event was not registered.

Primary efficacy outcomes were analyzed for pre-planned variables and the analysis was based on the principle of counting data from all patients starting treatment. Data analysis for all patients starting treatment included all randomized subjects and all events over the time period from randomization to completion of the trial. The trials were completed on May 31, 2012. A secondary analysis of clinical outcomes for preplanned variables was also performed on patients who were observed to be able to tolerate treatment and agreed with treatment after the first month of randomization. This analysis included all events over the time period from randomization to patient withdrawal from colchicine treatment.

Time to first event for all clinical outcomes was presented using a Kaplan-Meier plot.

The primary effectiveness of clinical outcomes was analyzed using the Cox proportional hazards model, including the treatment group, i.e. control group or colchicine treatment group. Secondary clinical outcomes were analyzed in a similar manner. In addition, the primary analysis was stratified by sex, age, diagnosis of diabetes, prior myocardial infarction, unstable angina, prior coronary bypass surgery, coronary angioplasty, and treatment with aspirin, clopidogrel, or both, and high-dose statin treatment (defined as statin dose equivalent to 40 mg atorvastatin or more), beta-blockers, calcium channel blockers, and ACE inhibitors.

Results.

The studied population. Between August 2008 and May 2010, 901 patients with a diagnosis of stable coronary heart disease who underwent a standard outpatient cardiac examination were assessed according to the inclusion criteria for the trial. Among these patients, 297 (33%) did not meet the inclusion criteria, 72 patients (8%) refused to participate, and 532 patients (59%) were enrolled in the trials, with 250 enrolled patients randomized to control and 282 patients randomized to treatment group. Among the patients randomized to the treatment group, 32 (11%) developed early intolerance to treatment due to gastrointestinal side effects, and 7 patients subsequently refused treatment (FIG. 1). All 532 randomized patients completed the trial for a minimum of 24 months and a maximum of 44 months. The average duration of participation in the trial was 36 months.

Baseline characteristics for the randomized treatment groups are shown in Table 1. 1. Both groups were eligible for important clinical characteristics, although the majority of patients in the colchicine treatment group were taking calcium channel blockers and fewer patients were being treated with β-blockers. Nearly all patients in each group were on antithrombotic treatment and were taking high-dose statins.

Table 1

Study population

Control group, n(%) Treatment group, n(%) Total number 250 282 Average age 67±9.2 66±9.6 Men 222 (89) 251 (89) diabetics 69 (28) 92 (33) smokers 14(6) Yu(4) Postponement of AMI or NS 61 (24) 64 (23) US 39(16) 62 (22) PCA 138(55) 169 (60) Aspirin and/or fluoride (Plavix) 235 (94) 262 (93) dptl 24 (10) 38(13) high dose statins 235 (94) 271 (96) BB ¹ 178(71) 176 (62) BKK ² 25 (10) 52 (18) ACE 150(60) 155 (55)

1p<0.05.

² p<0.01 to compare distributions between treatment group and control group.

- 11 039635

History of MI or UA Myocardial infarction or unstable angina in anamnesis

CABG Coronary artery bypass grafting

RCA History of subcutaneous coronary angioplasty

DPTL Dual antithrombotic treatment (aspirin and clopidogrel)

BB Treatment (beta-blockers)

CCB Treatment with calcium channel blockers

ACE Treatment with ACE inhibitors

Late withdrawal from treatment. 30 patients discontinued colchicine treatment after a median of 2.36 years. 11 patients discontinued treatment due to unrelated comorbidity, 5 patients discontinued treatment voluntarily, and 14 patients (4.9%) discontinued treatment due to various adverse events that may have been drug-related, as described in table. 2.

Table 2

Refusal of treatment

P(%) Early withdrawal from treatment 32(11) Late withdrawal* 30(11) Unrelated comorbidity And (3.9) Refusal of treatment at the request of the patient 5(1.8) Identified side effects bowel disorder 7 (2.5) muscle pain 2 (0.90) Myositis 1 (<0.5) Rash 1 (<0.5) Alopecia 1 (<0.5) Itching 1 (<0.5) Peripheral neuritis 1 (<0.5)

* Refusal of treatment after 30 days. The median time to withdrawal from treatment was 2.36 years.

Clinical results. Primary outcomes were reported in 55/532 patients, including 15/282 (5.3%) patients in the colchicine group and 40/250 (16%) patients in the control group (hazard ratio (HR) 0.33, confidence interval (CI) 95%, 0.18-0.59, p<0.001, number of patients requiring treatment was 11). For primary clinical outcomes, a sensitivity analysis was performed, adjusted for calcium channel blockers and β-blocker treatment. The results are consistent with those of the primary analysis.

In FIG. 2 shows the time it took to register the first clinical event in each treatment group. The effect of colchicine on primary clinical outcomes became apparent early on, and an increasing beneficial effect of colchicine was observed throughout the trial period. Results from the primary analysis were consistent across all subgroups studied (Fig. 3). Evidence of different treatment effects based on any clinical or therapeutic variable was not observed.

The decrease in the number of primary clinical outcomes was largely due to the decrease in the number of patients diagnosed with ACS, (13/282 (4.6%) vs. 34/250 (13.4%), risk ratio (HR) 0.33, 95% CI, 0.18-0.63, p<0.001). Out-of-hospital cardiac arrest and non-cardioembolic ischemic stroke were reported in rare cases, and the number of such events was also lower in the treatment group (Table 3).

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Table 3

Primary clinical results Control group (n=250) n, % Primary clinical 40(16) results <0.001 and their components SR treatment group 95% CI (n=282) n, % 15 (5.3) 0.33 R 0.18-0.59 Primary clinical outcome components Acute coronary syndrome <0.001 VN cardiac arrest 0.534 Non-cardioembolic stroke 0.184 34(13.6) 2 (0.8) 4(1.6) 13 (4.6) 1 (0.35) ¹ 1 (0.35) 0.33 0.47 0.23 0.18-063 0.04-5.15 0.03-2.03 OKS components Stent-related 4 (1.6) Non-stent related 30(12) <0.001 AMI not associated with 14 (5.6) stenting 0.014 NA unrelated 16 (12) stenting 0.011 VN Community-acquired 4 (1.4) 9 (3.2) 4 (1.6) 5 (2.4) No data 0.26 0.12-0.55 0.25 0.08-0.76 0.27 0.10-0.75

ACS Acute coronary syndrome

AMI Acute myocardial infarction

NS Unstable angina 'Non-lethal

Among 47 patients diagnosed with ACS, 8 patients (17%) (2 patients in each group had acute stent thrombosis and 2 patients in each group had significant intra-stent stenosis) had stent-related disease. Additional analysis confirmed that patients randomized to treatment were less likely to have ACS not related to stent-related disease (9/282 (3.2%) vs. 30/250 (12%), ratio risks 0.26, CI 95%, 0.12-0.55, p<0.001), while ACS was associated with AMI (4/282 (1.4%) vs. 14/250 (5.6%) , hazard ratio 0.25, 95% CI, 0.08-0.76, p=0.014) or NA (5/282 (1.8%) vs. 16/250 (6.4%), hazard ratio 0.27, 95% CI, 0.10-0.75, p=0.011, Figure 4, Table 3.)

Of 39 patients randomized to treatment who did not receive treatment after the first month due to early intolerance or refusal of treatment, 4 patients (10%) had ACS due to acute stent thrombosis (n=11) and NS (n=3). Patients who agreed with treatment and who were observed to tolerate treatment after the first month of randomization had significantly fewer events compared to patients in the control group (11/243 (4.5%) vs. 40/250 (16%) , hazard ratio 0.29, 95% CI, 0.15-0.56, p<0.001). The results of all analyzes performed during the treatment period are consistent with the results based on the statistical analysis of all randomized patients (Table 4).

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Table 4

Primary clinical outcomes and their components (analysis during treatment)

Primary clinical outcome <0.001 Control group (n=250) n, % 40(16) Treatment group (n=243) n, % 15(5.3) SR CI 95% 0.29 R 0.15-0.56 Components of Primary Clinical Outcomes Control group (n=250) P, % Treatment group (n=243) n, % SR CI 95% R Acute coronary syndrome <0.001 34(13.6) 9 (4.6) 0.28 0.13-0.58 VN cardiac arrest 0.622 2 (0.8) 1 (0.35) ¹ 0.55 0.05-6.03 Non-cardioembolic stroke 0.242 OKS components 4(1.6) 1 (0.35) 0.27 0.03-2.42 Due to stenting 4(1.6) 3 (1.4) There is no data Not associated with stenting <0.001 30(12) 6 (3.2) 0.21 0.03-0.50 AMI not associated with stenting 0.033 14 (5.6) 4 (1.6) 0.30 0.10-0.91 NS not associated with stenting 0.007 VN OKS AMI NA 'Illegal 16 (12) 2 (2.4) In non-hospital Acute coronary syndrome Acute myocardial infarction Unstable angina 0.13 0.03-0.57

10 patients in the control group died compared to 4 patients in the colchicine treatment group. Of the 10 deaths in the control group, 5 were suspected to be due to heart problems, 2 were community-acquired cardiac arrests, 2 were due to cardiogenic shock after myocardial infarction, and 1 was due to coronary artery bypass surgery. In the colchicine-treated group, all 4 patient deaths were due to causes unrelated to heart problems.

The results of the LoDoCo trial showed that the inclusion of treatment with 0.5 mg/day colchicine in addition to standard treatment in patients diagnosed with stable coronary heart disease significantly reduced the risk of cardiovascular events, including ACS, out-of-hospital cardiac arrest, and non-cardioembolic ischemic stroke. The benefit of colchicine was achieved against the background of standard use of effective secondary prophylactic treatments, including treatment with high doses of statins, as evidenced by the low incidence of events in the control group. The effect of colchicine incorporation became evident early in treatment, continued to increase over time, and was mainly due to a decrease in non-stent related ACS.

For specialists in the relevant field of technology it seems obvious that numerous variations and modifications are possible in addition to those already described in this context, which do not go beyond the basic concepts of the invention. All such variations and modifications should be considered within the scope of the present invention, which should be determined based on the above description.

CLAIM

Claims (14)

CLAIM 1. A method for treating and/or preventing a cardiovascular event in a subject in need thereof, comprising administering 0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof, or any - 14 039635 their combination to a subject once a day, where the cardiovascular event is one or more of an acute coronary syndrome, out-of-hospital cardiac arrest or non-cardioembolic ischemic stroke and where colchicine, its pharmaceutically acceptable salt, or any combination thereof is contained in a composition representing as a single tablet or liquid formulation. 2. The method according to claim 1, further comprising the joint introduction to the subject of the second agent for the treatment and/or prevention of a cardiovascular event in the subject, where the second agent is a statin; where the statin is one or more of atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin and pravastatin. 3. The method according to claim 1, further comprising the joint introduction to the subject of the second agent for the treatment and/or prevention of a cardiovascular event in the subject, where the second agent is an antithrombotic agent; wherein the antithrombotic agent is one or more of an irreversible cyclooxygenase inhibitor, an adenosine diphosphate (ADP) receptor inhibitor, a phosphodiesterase inhibitor, an IIB/IIIA glycoprotein inhibitor, an adenosine reuptake inhibitor, a thromboxane inhibitor, and a thromboxane receptor antagonist. 4. The method of claim 1 wherein the subject is co-administered with a second agent for the treatment and/or prevention of atherosclerotic vascular disease, wherein the second agent is a statin or an antithrombotic agent; where the statin is one or more of atorvastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin, pitavastatin and pravastatin and where the antithrombotic agent is one or more of an irreversible cyclooxygenase inhibitor, an adenosine diphosphate (ADP) receptor inhibitor, a phosphodiesterase inhibitor, a glycoprotein IIB/IIIA inhibitor , an adenosine reuptake inhibitor, a thromboxane inhibitor, and a thromboxane receptor antagonist. 5. The method of claim 1 wherein the subject has or has been diagnosed with atherosclerotic vascular disease. 6. The method of claim 1, wherein the subject is a human. 7. A method for reducing the long-term risks associated with atherosclerotic vascular disease in a subject in need thereof, comprising administering 0.5-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof, or any combination thereof, to the subject once a day where the subject is diagnosed clinically stable atherosclerotic vascular disease. 8. The method of claim 7 wherein the subject is a human. 9. The method of claim 7 wherein colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is administered for a minimum of 24 months. 10. The method of claim 7, wherein the subject also has stable coronary heart disease and/or cholesterol crystal-induced plaque inflammation. 11. The method of claim 10, wherein the stable coronary heart disease is clinically stable coronary heart disease. 12. The method according to any one of claims 7 to 10, wherein colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is contained in the composition, wherein the composition is administered in the form of a tablet, capsule, liquid composition, gel, or powder form intended for single administration per day. 13. The method of claim 12, wherein the composition is liquid. 14. The method of any one of claims 7-13, wherein colchicine, a pharmaceutically acceptable salt thereof, or any combination thereof is contained in the composition, wherein the composition further comprises a therapeutically effective amount of a statin and an antithrombotic agent.