WO2009100534A1 - Thérapie de combinaison pour traiter des troubles vasculaires - Google Patents

Thérapie de combinaison pour traiter des troubles vasculaires Download PDF

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Publication number
WO2009100534A1
WO2009100534A1 PCT/CA2009/000175 CA2009000175W WO2009100534A1 WO 2009100534 A1 WO2009100534 A1 WO 2009100534A1 CA 2009000175 W CA2009000175 W CA 2009000175W WO 2009100534 A1 WO2009100534 A1 WO 2009100534A1
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triflusal
stroke
combination
aspirin
dipyridamole
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PCT/CA2009/000175
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English (en)
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Wasimul Haque
Neil Dunwald
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Kardiatech, Inc.
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Priority to US12/541,886 priority Critical patent/US20100069326A1/en
Publication of WO2009100534A1 publication Critical patent/WO2009100534A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • the invention relates to methods, uses, and compositions comprising pharmaceutical compositions of at least one antiplatelet agent, 2-acetoxy-4- trifluoromethylbenzoic acid, also known as triflusal.
  • the invention may also include other antiplatelet agents and/or agents for treating vascular disorders, including but not limited to dipyridamole or cilostazol; P 2 Y 12 inhibitors, such as clopidogrel or prasugrel; COX-2 inhibitors, such as celecoxib; and anticoagulants, such as enoxaparin.
  • the methods, uses, and compositons of the present invention may be used for secondary prevention of stroke, and those caused by prothrombotic states induced by platelet aggregation and/or an activated coagulation cascade, among other diseases and conditions.
  • Cardiovascular and cerebrovascular diseases are the leading cause of death in the world. Several factors that lead to cardiovascular or cerebrovascular disorders are also known to increase the susceptibility of individuals to stroke.
  • Cerebrovascular disease includes any abnormality of the brain resulting from a pathologic process of a blood vessel.
  • a pathologic process of a blood vessel includes any one or more of the following: an occlusion of a blood vessel lumen by thrombus or embolus, a rupture of a blood vessel, an altered permeability of a blood-vessel wall, and increased viscosity or other change in the quality of blood.
  • Cerebrovascular disease is typically readily diagnosable because of how it manifests. Cerebrovascular disease typically manifests as a stroke.
  • a stroke can be characterized as a sudden nonconvulsive, focal neurologic deficit. That is, stroke can be characterized as the death of brain tissue that results from lack of blood flow and insufficient oxygen to the brain. After heart disease and cancer, stroke is the leading cause of death in the United States.
  • a stroke can be ischaemic or hemorrhagic.
  • an ischaemic stroke the blood supply to part of the brain is reduced or terminated either by a blood clot that blocks a blood vessel or by atherosclerosis. Reducing or terminating blood flow to the brain is known as cerebral ischemia. Cerebral ischemia can last for seconds to minutes (Transient Ischaemic attack, mini-stroke), and when cerebral ischemia occurs for more than a few minutes, infarction of brain tissue results.
  • a blood vessel can be blocked by a blood clot that arises from thrombus or embolus.
  • cerebral ischemia can also arise from the failure of circulation and hypotension from severe and prolonged cardiac decompensation or shock.
  • the brain In a hemorrhagic stroke, the brain is damaged by a blood vessel bursting, which prevents normal blood flow and allows blood to leak into an area of the brain. In some instances, the blood leaks from a small artery. When blood leaks into the brain, a hematoma is formed in the brain and blood can spread into ventricles and subarachnoid space.
  • Acute ischaemic stroke is a notoriously difficult to treat (Therapeutic Strategies For The Treatment Of Stroke, A. Richard Green and Ashfaq Shuaib, Drug Discovery Today Volume 11 , Numbers 15/16 August 2006). Consequently much of the clinical effort is currently directed toward strategies for preventing recurrence of stroke.
  • the pharmacological properties of triflusal offer potential benefits in the targeting of specific patient populations, e.g., those with relatively benign bleeding profile or increased vasodilation. Such properties may be complementary, additive, or synergistic with those of its partner drug.
  • a vulnerable plaque ruptures, factors within the vessel wall, such as collagen or von Willebrand Factor are exposed to circulation and cause platelets to adhere.
  • the coagulation cascade is initiated and very often the vessel becomes occluded, causing non-Q wave myocardial infarction, myocardial infarction, transient ischaemic events, and stroke.
  • Activation of platelets has also been implicated in coronary artery disease, peripheral artery disease, unstable angina, asthma, rhinitis, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, and atherosclerosis.
  • Aspirin is one of the most frequently used oral agents for retarding platelet aggregation for the purpose of forestalling occlusive events. It has been reported that as many as 40% of humans using standard doses of aspirin have some degree of difficulty achieving appropriate inhibition without adverse events. One key to replacing aspirin in therapy is to find agents that will, by themselves or in combination, safely and effectively provide the necessary degree of platelet inhibition.
  • the invention relates to compositions and methods of treating a thrombotic or thromboembolic event in a patient using antiplatelet and/anticoagulant agents.
  • the compositions and methods involve aspirin-free combinations of two or more such agents.
  • the patient is aspirin resistant.
  • the patient is at risk of aspirin- induced bleeding.
  • Some embodiments of the invention include a composition and method of treating a thrombotic or thromboembolic event in a patient in need of such treatment comprising administering a therapeutically effective amount of triflusal and administering a therapeutically effective amount of at least one additional agent.
  • Some embodiments of the invention may include treating post-thrombotic or post-thromboembolic event.
  • a triflusal/dipyridamole or triflusal/cilostazol are drug combinations in which both components act upon the same pathways in an additive or synergistic manner.
  • Triflusal is known to have a lower haemorrhagic effect than aspirin as well as to act as a phosphodiesterase inhibitors. The latter effect is additive or synergistic with dipyridamole or cilostazol.
  • Cilostazol is not known to cause headaches like dipyridamole. Both combinations are aspirin free so that aspirin non-responders may benefit. Patients who have suffered intermittent claudication or ischaemic stroke will benefit from reduced frequency of bleeding events and the vasodilator/ synergies.
  • the invention involves the use of combinations of antiplatelet agents to improve over current therapies.
  • the inventors seek to prevent cardiovascular and cerebrovascular diseases from occurring and ameliorating the consequences of pathological cardiovascular and cerebrovascular events.
  • a specific object of this invention is to provide alternate medications that will improve neuroprotective and vasodilating properties as compared to products on the market.
  • a final objective of this invention is to provide alternate medications that reduce bleeding events.
  • triflusal/dipyridamole may have a theoretically superior neuroprotection profile, a potentially better inhibition of neurological cyclooxygenase, COX-3, and lower vasoconstrictive properties than either aspirin or aspirin in combination with dipyridamole.
  • Triflusal is five times more potent than aspirin as inhibitor of cAMP phosphodiesterase.
  • the synergic or additive effects on cAMP levels may allow the combination to contain a reduced dose of dipyridamole than that used in the current product on the market.
  • Triflusal also has favorable neuroprotective effects in stroke patients by eliciting greater inhibitory effects of cytokine IL-6.
  • Triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), a 4 fluoromethyl derivative of salicylate acid, and it's active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid (HTB) are direct inhibitors of cyclooxygenase-2 (COX-2) and indirect inhibitors of NFKB (Bayon et al, 1999), whereas aspirin is a COX-l/COX-2 inhibitor. Both triflusal and aspirin have properties that may help protect the brain against neuroinflammatory and apoptotic mechanisms in Cl. It has been demonstrated in the rat middle cerebral artery occlusion (MCAO) model of stroke that a dose of 30 mg/kg for triflusal and aspirin were equally effective in reducing infarct size (Whiteheads, etal, 2007).
  • MCAO middle cerebral artery occlusion
  • Dipyridamole has antiplatelet and vasodilator properties with a mechanism of action that may be related to inhibition of platelet phosphodiesterase, stimulation of prostacyclin, or inhibition of adenosine uptake (Sudlow, et al, 2005). It has been demonstrated that the combination of aspirin and dipyridamole is more effective than aspirin alone in the secondary prevention of stroke (Halkes et al, 2008). Thus, it is possible that a combination of dipyridamole and triflusal might be an effective treatment for prevention of recurrent stroke.
  • Triflusal/clopidogrel combination to treat unstable angina or non-ST elevation myocardial infarction.
  • Triflusal/low-molecular-weight heparin combination for the treatment of patients with atrial fibrillation
  • While this combination may also find use in treating acute coronary syndrome, deep-vein thrombosis, pulmonary embolism, and cardiopulmonary bypass surgery, patients with chronic atrial fibrillation have few good options for long-term preventive therapy. Those with a low risk are often treated with anticoagulant plus aspirin while higher risk patients are treated with warfarin and an anticoagulant. Patients in the low risk group may benefit from Triflusal/clopidogrel combination administration while those in an acute setting group should benefit from Triflusal/low-molecular-weight heparin combination.
  • Triflusal/celecoxib for treatment of patients with Peripheral Artery Disease Vioxx (valdecoxib), Bextra (Rofecoxib), Arcoxia (etoricoxib) and Celebrex (celecoxib) are four selective COX-2 inhibitors to make it to market (Comp. Ther. 2006; (32(4) incorporated by reference in its entirety). The former two have been withdrawn from market because of reports of adverse cardiovascular events.
  • One theory, to which the inventors do not wish to be bound, has it that endothelial cells lining blood vessels express COX-2, and, by selectively inhibiting it, prostaglandins (specifically PGI 2 ; prostacyclin) are downregulated relative to thromboxane levels.
  • the invention is compositions and methods for treating vascular disorders and/or conditions that involve administering a first agent comprising triflusal (or a triflusal analog or derivative) in combination with at least one other active agent (e.g., a second active agent).
  • the second active agent may be an anti-platelet agent.
  • an antiplatelet agent affects platelet function, typically by inactivating platelets, or inhibits or reducing platelet activation, or by reducing or inhibiting platelet adhesion and/or aggregation.
  • the preferred triflusal derivative is HTB.
  • each agent works together to provide a therapeutic benefit for the patient, such as treating a condition or disease, or relieving one or more symptoms, or treating one or more side-effects of the other agent.
  • the inventors have created four combination drug products, a triflusal/clopidogrel combination to treat unstable angina or non-ST elevation myocardial infarction, a triflusal/low-molecular-weight heparin combination for the treatment of patients with atrial fibrillation, a triflusal/celecoxib for treatment of patients with peripheral artery disease, and a triflusal/phosphodiesterase inhibitor combination for the secondary prevention of stroke.
  • the second active agent may be any additional agent that provides a therapeutic benefit.
  • additional agents include but are not limited to HTB; a GPIIb/111a inhibitor such as abciximab, eptifibatide, tirofoban, and lamifiban; , an ADP receptor antagonist, such as ticlopidine, prasugrel, or clopidogrel; or a phosphodiesterase inhibitor, such as dipyridamole or cilostazol, and Aggrenox.®; or a selective serotonin reuptake inhibitor.
  • compositions and methods of treating a thrombotic or thromboembolic event in a patient in need of such treatment comprising administering a therapeutically effective amount of a first agent (e.g., triflusal or HTB) in combination with a therapeutically effective amount of an anticoagulant.
  • a first agent e.g., triflusal or HTB
  • Some embodiments of the invention include administering a first active agent (e.g., triflusal or HTB), an anticoagulant, and a thrombolytic agent.
  • a first active agent e.g., triflusal or HTB
  • an anticoagulant e.g., a thrombolytic agent
  • anticoagulant compounds include, but are not limited to unfractionated heparin, hirudin, an antithrombin (e. g. human antithrombin III), sulodexide, a low molecular weight heparin (e.g., bemiparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin).
  • Some embodiments of the invention include administering a first agent in combination with a low molecular weight heparin.
  • enoxaparin is an exemplary low molecular weight heparin.
  • triflusal and a low molecular weight heparin such as enoxaparin may be combined for the treatment of acute coronary syndrome and/or to treat atrial fibrillation.
  • Some embodiments of the invention include administering the first active agent (e.g., triflusal or HTB) in combination with a P 2 Y1 2 inhibitor.
  • the P2Y12 inhibitor may be selected from any of the exemplary compounds as follows: clopidogrel, ticlopidine, or prasugrel.
  • the preferred P 2 Y 12 inhibitor is clopidogrel.
  • the first agent and the P 2 Y1 2 inhibitor such as clopidogrel are combined for the treatment of a coronary condition, such as acute coronary syndrome, unstable angina, and/or non-ST elevation myocardial infarction.
  • Some embodiments of the invention include administering the first active agent (e.g., trifludal or HTB) in combination with a selective COX-2 inhibitor, e.g., one that does not inhibit COX-1.
  • a selective COX-2 inhibitor e.g., one that does not inhibit COX-1.
  • the COX-2 inhibitors are not selective inhibitors.
  • Exemplary non-selective inhibitors include, but are not limited to aspirin, ibuprofen, naproxen, indomethacin, and diclofenac.
  • the selective COX-2 inhibitors may be selected from any of the exemplary compounds as follows: valdecoxib, rofecoxib, eetoricoxib and celecoxib.
  • the preferred COX-2 inhibitor is celecoxib.
  • triflusal or HTB and celecoxib are combined for the treatment of peripheral artery disease.
  • the first agent combined with the second agent may be used to inhibit thrombosis in patients.
  • the first active agent is triflusal or HTB.
  • the second active agent may be a phosphodiesterase inhibitor, including but not limited to dipyridamole or cilostazol.
  • the dipyridamole may be formulated to achieve extended release.
  • the combination of triflusal and dipyridamole may be used to prevent stroke and/or to treat stroke patients at risk of aspirin-induced bleeding.
  • triflusal and dipyridamole may be used in patients who are non-responders to aspirin, or aspirin resistant; or in the secondary prevention of stroke in patients who are at risk of aspirin- induced bleeding, are non-responders, or are aspirin resistant;
  • the first agent combined with the second agent may be used for diabetic hypertensive patients, in type Il diabetics (non-insulin dependent diabetes mellitus, NIDDM, or adult-onset diabetes).
  • type Il diabetics non-insulin dependent diabetes mellitus, NIDDM, or adult-onset diabetes.
  • various doses and frequency of doses may be used.
  • oral combinations may be administered in fixed dose formulations.
  • one or more of the agents in the combination will have a lower dose than the dose used in monotherapy.
  • the dose used to achieve a beneficial result is any dose and frequency of administration sufficient to provide a therapeutic benefit for the patient.
  • many factors may be involved in determining a proper dosage, including but not limited to the size and weight of the patient, the particular active agent or combination of active agents being used, and the age of the patient.
  • composition of the invention may include a pharmaceutically acceptable carrier, adjuvant or vehicle that may be administered to a subject, together with a combination of the present invention, and which does not destroy the pharmacological activity of the combination.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the compositions of the present invention include, but are not limited to, the following: ion exchangers, alumina, aluminum stearate, lecithin, self- emulsifying drug delivery systems ("SEDDS") such as d(-tocopherol polyethyleneglycol 1000 succinate), surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride,
  • compositions include those formulating the combination(s) of the invention with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses or polyethylene glycols. Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, maleic anhydride copolymer, and agents to control release such as polyacrylic copolymer. Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • Cyclodextrins such as .alpha.-, .beta.- and . gamma. -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and S-hydroxypropyl-.beta.-cyclodextrins, or other solubilized derivatives may also be used to enhance delivery of the combinations of the present invention.
  • the combination may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques; nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • the present combinations may, for example, be administered in a form suitable for immediate release, extended release or combinations thereof.
  • Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present combinations, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • the present combinations may also be administered liposomally.
  • the active substance can be utilized in a composition such as tablet, capsule, solution or suspension or in topical form. They may be combined in a conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., or with a topical carrier.
  • Anticoagulant refers to a molecule that interferes with the non-cellular participants of a coagulation cascade. Accordingly, they have very little direct effect on platelets.
  • Exemplary anticoagulants include Vitamin K antagonists (e.g. warfarin (Coumadin), acenocoumarol or phenprocoumon); Heparin, heparin combinations, and derivative substances (e.g.
  • heparin unfractionated heparin, heparin and hirudin, danaparoid
  • low molecular weight heparin e.g., bemiparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin sulodexide
  • Synthetic pentasaccharide inhibitors of factor Xa and antithrombin (e. g. human antithrombin III),
  • Antiplatelet agent refers to a pharmaceuticals used in primary and secondary prevention of thrombotic events that decreases platelet aggregation and inhibit thrombus formation.
  • the importance of inhibiting platelets lies in the fact that platelet adhesion to the endothelium is the initiating event in primary hemostasis. Accordingly, antiplatelet agents are effective in the circulation where anticoagulants have little effect.
  • Drugs considered to be antiplatelet agents are cyclooxygenase inhibitors (e.g. aspirin, triflusal); adenosine diphosphate (ADP) receptor inhibitors - (e. g. clopidogrel, Ticlopidine); phosphodiesterase inhibitors (e.g.
  • antiplatelet agents have more than one therapeutic property. For example, it is possible for one agent to be both a antiplatelet agent and a vasodilator.
  • Aspirin refers to a white, crystalline acetylated derivative of salicylic acid, CH 3 COOC 6 H 4 COOH, derived from salicylic acid and commonly used in tablet form to relieve pain (especially from headache, rheumatism, gout, neuralgia, etc.), fever, and inflammation. It is also used as an antiplatelet agent to slow clotting of the blood by inhibiting the aggregation of platelets. In long term antiplatelet therapy patients are normally prescribed enteric coated aspirin to forestall gastrointestinal bleeding.
  • Aspirin Resistance refers to the phenomenon whereby aspirin does not have as strong an effect on platelets as for others. Women are reportedly more likely to be resistant than men but there is currently no accepted method of determining who is resistant, known as "aspirin insensitivity”.
  • Aspirin Non-Responders refers to those patients who do not exhibit significant antiplatelet activity when treated with the standard dose.
  • Atherosclerosis is a chronic inflammatory disease affecting arterial blood vessels. It is a response in large part due to the deposition of lipoprotein plaques
  • CAD Coronary Artery Disease
  • COX-2 inhibitor refers to a molecule that inhibits the COX-2 enzyme to a higher degree than it inhibits the COX-1 enzyme. Ibuprofen, naproxen, indomethacin, diclofenac are drugs that perform this funtion. A selective COX-2 inhibitor inhibits the COX-2 enzyme while have little or no effect on the COX-1 enzyme. Examples of selective COX 2 inhibitors are valdecoxib, rofecoxib, eetoricoxib and celecoxib.
  • Heart attack myocardial infarction, AMI, Ml
  • AMI myocardial infarction, Ml
  • a heart attack may also occur when a coronary artery temporarily contracts or goes into a severe spasm, effectively shutting off the flow of blood to the heart. In either case, the resulting ischemia or oxygen shortage causes damage and potential death of heart tissue.
  • P 2 Y 12 inhibitor refers to a molecule that blocks the P2Y12 protein from acting on a chemoreceptor for adenosine diphosphate (ADP). It is found on the surface of blood platelet cells.
  • P 2 Y1 2 inhibitors are exemplified by clopidogrel, ticlopidine, or prasugrel.
  • Patients at risk of aspirin-induced bleeding refers to patients that have at least one factor that would place them at risk of bleeding due to aspirin-mediated antiplatelet therapy. These risk factors are generally: prior gastrointestinal bleeding events (e.g. ulcers); increased age; use of anticoagulants such as warfarin; use of corticosteroids; and concomitant use of increased dose or multiple non-steroidal antiinflammatory drugs.
  • Peripheral Artery Disease is a condition similar to CAD but occurring in arteries outside of the heart or brain.
  • PAD fatty deposits build up along the inner linings of the artery walls. These blockages restrict blood circulation, mainly in arteries leading to the kidneys, stomach, arms, legs and feet.
  • People with PAD often exhibit plaques in the arteries of the heart and brain. Because of this association, most people with PAD have a higher risk of death from heart attack and stroke.
  • “Strokes” are classified as either ischaemic or hemorrhagic, the former accounting for approximately 80% of all events.
  • Ischaemic stroke similar to heart attack, is caused by tan interruption of blood flow to the brain.
  • Thrombotic strokes are caused by a blood clot that forms in an artery directly leading to the brain. Embolic strokes occur when a clot develops somewhere else in the body and travels through the blood stream to the brain.
  • Hemorrhagic stroke - About 20% of strokes are hemorrhagic which means they are characterized by uncontrolled bleeding in the brain. This "flooding" of the brain kills brain cells. Subarachnoid hemorrhage is uncontrolled bleeding on the surface of the brain, in the area between the brain and the cranium. Intracerebral hemorrhage occurs when an artery deep within the brain ruptures. Both types of hemorrhage can be caused by structural problems with the blood vessels in the brain.
  • a thrombotic or thromboembolic event includes but is not limited to the following: atrial fibrillation, acute coronary syndrome including, unstable angina, acute myocardial infarction, ischaemic stroke, acute coronary ischaemic syndrome, thrombosis, thromboembolism, peripheral artery disease, deep vein thrombosis, arterial thrombosis of any vessel, catheter thrombotic occlusion, thrombotic occlusion and reocclusion, transient ischaemic attack, first or subsequent thrombotic stroke.
  • acute coronary syndrome including, unstable angina, acute myocardial infarction, ischaemic stroke, acute coronary ischaemic syndrome, thrombosis, thromboembolism, peripheral artery disease, deep vein thrombosis, arterial thrombosis of any vessel, catheter thrombotic occlusion, thrombotic occlusion and reocclusion, transient ischaemic attack, first or subsequent thrombotic stroke.
  • TIA Transient Ischaemic Attack
  • mini-stroke a temporary interruption of blood flow to the brain.
  • the symptoms are similar to an ischaemic stroke except they go away within a few minutes or hours.
  • a TIA is an important indicator of full-blown stroke risk; however, people frequently have a TIA without even knowing it. This detection problem leaves one estimates of the true size of population.
  • Vascular condition refers to a pathology of or about the vasculature of the circulatory system.
  • Specific exemplary conditions include Coronary Artery Disease (CAD); Acute Coronary Syndrome (ACS), including unstable angina and non-ST- elevated myocardial infarction; Acute Coronary Ischaemic Syndrome; first or subsequent thrombotic Stroke; Transient Ischaemic Attack (TIA); Peripheral Artery Disease (PAD); Deep Vein thrombosis (DVT); Atherosclerosis; Atrial Fibrillation. catheter thrombotic occlusion; thrombotic occlusion and reocclusion; and arterial thrombosis of any vessel.
  • CAD Coronary Artery Disease
  • ACS Acute Coronary Syndrome
  • TIA Transient Ischaemic Attack
  • PAD Peripheral Artery Disease
  • DVT Deep Vein thrombosis
  • Atherosclerosis Atrial Fibrillation. catheter thrombotic occlusion; thrombotic
  • Vasodilator refers to a drug or chemical that relaxes the smooth muscle in blood vessels, which causes them to dilate.
  • This group includes Alpha-adrenoceptor antagonists (alpha-blockers); Angiotensin converting enzyme (ACE) inhibitors; Angiotensin receptor blockers (ARBs); ⁇ 2-adrenoceptor agonists ( ⁇ 2-agonists); Calcium-channel blockers (CCBs); Centrally acting sympatholytics; Direct acting vasodilators; Endothelin receptor antagonists; Ganglionic blockers; Nitrodilators; Phosphodiesterase inhibitors; and Potassium-channel openers. Most vasodilators exhibit pharmacological properties as mentioned above but dipyridamole or cilostazol also act as antiplatelet agents.
  • Triflusal is 2-acetoxy-4-trifluoromethylbenzoic acid, generally having the following formula:
  • HTB is hydroxyl trifluoromethyl benzoic acid, a metabolite of Triflusal, and generally having the following formula:.
  • Dipyridamole is 2- ⁇ [9-(bis(2-hydroxyethyl)amino)-2,7-bis(1-piperidyl)- 3,5,8,10 tetrazabicyclo [4.4.0]deca-2,4,7,9,11-pentaen-4-yl]-(2-hydroxyethyl)amino ⁇ ethanol
  • Cilostazol. is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]- 3,4-dihydro-2(1 H)-quinolinone
  • Clopidogrel. is (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin- 5(4H)-yl)acetate which are typically used to inhibit platelet aggregation.
  • Clopidogrel Celecoxib and other NSAIDS described in publications such as U. S. Patent 6,417,204, include 4-[5-(4-methylphenyl)-3-(trifluoromethyl) pyrazol-1-yl]benzenesulfonamide which are typically used to control pain and inflammation.
  • Lorenzo P Lizasoain I. Neuroprotective effect of aspirin by inhibition ofglutamate release after permanent focal cerebral ischaemia in rats. JNeurochem 2001 October;79(2):456-9.
  • mice were randomly divided into three treatment groups (n 5-7 for each group). Prior to and following surgery rats were housed in single cages (12/12h light/dark cycle) and were fed at libitum. Prior to surgery, all rats were anaesthetized with a single dose of sodium pentobarbital (60 mg/kg ip) and placed in a David Kopf stereotaxic apparatus. Rectal temperatures were monitored and maintained constant at 37 0 C by a heating pad while the rats were under anesthesia. The right MCA was exposed. The MCA was permanently occluded at 2 points using thermal coagulator, one above and one below the inferior cerebral vein.
  • Results are expressed as mean ⁇ SEM of each measure.
  • the volumes of the infarcts for each of the groups were compared by Student's unpaired two-tailed t tests. Significance was set at /KO.05. Correlations between parameters were tested by linear regression analysis.
  • the unilateral occlusion of the right MCAO resulted in circumscribed infarcts restricted to the right cortex and striatum. No injury was observed in the contralateral hemisphere.
  • the infarct volume in rats receiving vehicle treatment immediately after MCAO was 106.22 ⁇ 10 mm 3 .
  • the infarct volume in the animals treated with triflusal alone (30 mg/kg) or triflusal combined with dipyridamole (30 mg/kg of triflusal plus 200 mg/kg of dipyridamole) after MCAO were 73.59 ⁇ 7.0 and 81.13 ⁇ 5.3 mm 3 , respectively (Table 1.).
  • a combination of triflusal and dipyridamole at lower concentrations may be an effective treatment strategy based on what is known about mechanisms of neuroprotection.
  • the literature indicates that triflusal has a lower haemorrhagic effect than aspirin and is a more direct inhibitor of NFkappa B, which makes it a reasonable choice for further experimentation. Further investigations may involve Neurological Deficit Evaluation and rat tail bleeding experiments.
  • a detailed clinical outline monograph will be submitted to regulatory agencies such as the Food and Drug Administration of the United States or the Health Protection Branch of Canada to conduct a Phase I Exploratory trial that will determine various pharmacokinetic/pharmacodynamic parameters of the triflusal, dipyridamole, and the combination. Subject to regulatory advice, the trial will proceed with perhaps three arms of five individuals. The pharmacokinetic/pharmacodynamic data will then allow creating three or four specific oral formulations of the combination. These combinations will be subjected to humans to select one, which will have the desired safety to efficacy profile. The selected formulation will proceed through the next clinical trial process and be compared to Aggrenox, in diabetic/hypertensive patient populations who are at risk for stroke.
  • Cilostazol has been shown to improve cerebral blood flow and is already approved for use in for the prevention of recurrent stroke in some jurisdictions ⁇ Journal of Stroke and Cerebrovascular Diseases, Vol. 15, No. 6 (November-December), 2006: pp 273-276).
  • a detailed clinical outline monograph will be submitted to regulatory agencies such as the Food and Drug Administration of the United States or the Health Protection Branch of Canada to conduct a Phase I Exploratory trial a Phase I Exploratory trial that will determine various pharmacokinetic/pharmacodynamic parameters of the triflusal, cilostazol, and the combination. Subject to regulatory advice, the trial will proceed with perhaps three arms of five individuals. The pharmacokinetic/pharmacodynamics data will allow designing three or four specific oral formulations of the combination. These combinations will be subjected in humans to select one, which will have the best safety/efficacy profile. The selected formulation will proceed through the next clinical trial process and compared to Aggrenox in diabetic hypertensive patient populations who are at high risk for stroke.
  • Cilostazol is currently approved for the treatment of claudication and there is evidence that treatment of such at risk groups may reduce the risk of stroke (Journal of Stroke and Cerebrovascular Diseases, Vol. 17, No. 3 (May-June), 2008: pp 129-133).
  • MCAO middle cerebral artery occlusion
  • Rat AD model Male Wistar rats will be randomly divided into treatment groups. Prior to and following surgery rats will be housed in single cages (12/12h light/dark cycle) and will be fed at libitum. Prior to surgery, all rats will be anaesthetized with a single dose of sodium pentobarbital (40 mg/kg ip) and placed in a David Kopf stereotaxic apparatus. Rectal temperature will be monitored and maintained constant at 37 0 C by a heating pad while the rats were under anesthesia. The right MCA will be exposed. The MCA will be permanently occluded at 2 points, one above and one below the inferior cerebral vein. Immediately following surgery, rats will receive one of the following treatments:
  • Infarct Volume Assessment Serial brain sections will be then examined under a light microscope (Leitz Diaplan, Leica Canada, Willowdale ON, Canada), and the areas of infarcted tissue will be measured (SigmaScan Pro 5.0, SPSS Inc., Chicago IL, USA). In addition, the hemispheric areas of each tissue section will be measured to account for any brain swelling that might have occurred following cerebral ischemia. Infarct size for each section will be calculated as the ratio of the contralateral to ipsilateral hemisphere multiplied by the area of the infarct. The volume of the infarct will be calculated in mm 3 by integrating the infarct sizes for each of the tissue sections that contained infarcted tissue. Behavioral.
  • the staircase test for fine motor skill will be used to determine the functional changes following the MCAO and treatment for each of the groups.
  • rats will be placed into the Montoya Staircase apparatus at the same time every day for 8 days (days -8 through -1) and will be allowed to perform the test for 20 minutes. Rats will be food deprived for 1 day (day -9) prior to testing as well as on day -8. On days -7 though -1 , rats will be fed 10 g of their normal chow so that they maintained their body weight at approximately 85 %.
  • Three Noyes precision food pellets Research Diets Inc., New Brunswick, New Jersey; PFA/100045
  • Pellets eaten will be recorded from each well.
  • Re-testing trials which will be done 7 days after the surgical procedures (day 0), will be performed for 8 days in the same way as the training trials (days 8 through 15).
  • cytokines eg. IL-1 ⁇ , IL-6, TNF ⁇ or others identified by the arrays
  • cytokines eg. IL-1 ⁇ , IL-6, TNF ⁇ or others identified by the arrays
  • GFAP reactive astrocytes
  • OX-6 microglia
  • COX-2 the inflammatory transcription factor
  • NFKB the inflammatory transcription factor
  • Neuronal degeneration will be examined using vertebrate neuron-specific nuclear protein NeuN (Neuronal Nuclei) and anti Hu.
  • AD-like pathology will be determined using immunohistochemistry for APP, A ⁇ , TAU-2, and congophillic A ⁇ deposition with congo red.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Vascular Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)

Abstract

L'invention porte sur des compositions pharmaceutiques et sur des procédés pour traiter des troubles ou états vasculaires, comprenant la combinaison de triflusal ou d'un métabolite de celui-ci et d'un second agent actif choisi dans le groupe constitué par un inhibiteur GPIIb/IIIa, un antagoniste du récepteur ADP, un inhibiteur de la phosphodiestérase et un inhibiteur sélectif de la réabsorption de sérotonine. Au moins un anticoagulant et/ou un agent thrombolytique sont facultativement présents. L'état vasculaire préféré qui est traité est l'accident vasculaire cérébral.
PCT/CA2009/000175 2008-02-14 2009-02-13 Thérapie de combinaison pour traiter des troubles vasculaires WO2009100534A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017810A1 (fr) * 2009-08-14 2011-02-17 Kardiatech, Inc. Polythérapie pour traiter des troubles vasculaires
WO2011036533A1 (fr) 2009-09-23 2011-03-31 Glenmark Pharmaceuticals Limited Composition pharmaceutique contenant du prasugrel et du triflusal
US20120178777A1 (en) * 2009-10-15 2012-07-12 Guizhou Liansheng Parmaceutical Co., Ltd. Medicaments for Inhibiting Thrombus Formation

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US20050165030A1 (en) * 2001-12-27 2005-07-28 Yongge Liu Pharmaceutical compositions comprising a multifunctional phosphodiesterase inhibitor and an adenosine uptake inhibitor
CA2640472A1 (fr) * 2006-02-09 2007-08-16 Teva Pharmaceutical Industries Ltd. Formulations a liberation prolongee de dipyridamole et leur procede de preparation

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US4096252A (en) * 1976-06-10 1978-06-20 J. Uriach & Cia S.A. 4-Trifluoromethylbenzoic acid derivatives as thromboembolic agents
US20020013343A1 (en) * 1999-05-17 2002-01-31 Serebruany Victor L. Methods of inhibiting platelet activation with selective serotonin reuptake inhibitors
US20050165030A1 (en) * 2001-12-27 2005-07-28 Yongge Liu Pharmaceutical compositions comprising a multifunctional phosphodiesterase inhibitor and an adenosine uptake inhibitor
US20030199457A1 (en) * 2002-04-17 2003-10-23 El-Naggar Mawaheb M. Prevention and treatment of thromboembolic disorders associated with arterial & venous thrombosis
US20040214802A1 (en) * 2003-02-13 2004-10-28 Boehringer Ingelheim International Gmbh Dipyridamole, acetylsalicylic acid, and angiotensin II antagonist pharmaceutical compositions
CA2640472A1 (fr) * 2006-02-09 2007-08-16 Teva Pharmaceutical Industries Ltd. Formulations a liberation prolongee de dipyridamole et leur procede de preparation

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CRAIG ET AL., MODEM PHARMACOLOGY, 1994 *
GARCIA-RAFANELL ET AL.: "Effect oftriflusal and other salicyclic acid derivatives on cyclic AMP levels in rat platelets", ARCH INT PHARMACODYN, vol. 284, 1986, pages 155 - 165 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017810A1 (fr) * 2009-08-14 2011-02-17 Kardiatech, Inc. Polythérapie pour traiter des troubles vasculaires
WO2011036533A1 (fr) 2009-09-23 2011-03-31 Glenmark Pharmaceuticals Limited Composition pharmaceutique contenant du prasugrel et du triflusal
US20120178777A1 (en) * 2009-10-15 2012-07-12 Guizhou Liansheng Parmaceutical Co., Ltd. Medicaments for Inhibiting Thrombus Formation
US8921390B2 (en) * 2009-10-15 2014-12-30 Guizhou Liansheng Pharmaceutical Co. Ltd. Medicaments for inhibiting thrombus formation
KR101500815B1 (ko) * 2009-10-15 2015-03-09 구이조우 리안쉥 파머슈티컬 컴퍼니 리미티드 혈전형성을 억제하는 약물

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