WO2014209092A1 - Correcteur de dysfonction endothéliale - Google Patents

Correcteur de dysfonction endothéliale Download PDF

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Publication number
WO2014209092A1
WO2014209092A1 PCT/LV2014/000006 LV2014000006W WO2014209092A1 WO 2014209092 A1 WO2014209092 A1 WO 2014209092A1 LV 2014000006 W LV2014000006 W LV 2014000006W WO 2014209092 A1 WO2014209092 A1 WO 2014209092A1
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Prior art keywords
thrombosis
meldonium
hmg
acid addition
coa reductase
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PCT/LV2014/000006
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English (en)
Inventor
Ivars Kalvins
Anatololijs BIRMANS
Maris Veveris
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Tetra, Sia
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Publication date
Application filed by Tetra, Sia filed Critical Tetra, Sia
Publication of WO2014209092A1 publication Critical patent/WO2014209092A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates generally to agents improving the condition caused by endothelial dysfunction. More specifically it relates to second medical use of meldonium acetylsalicylic acid additional salt combination with a statin for treating thrombosis.
  • Thrombosis and thrombotic or thromboembolic complications are at present one of the leading causes of lethality. This indicates the actuality of the problem and continuing lack of safe means for solving said problem. New antithrombotic agents with wider safety margin and less pronounced adverse effects (bleeding etc.) are still required.
  • Haemostatic system comprises platelets, blood coagulation factors and endothelial cells, lining the blood-vessels. In normal condition the integrity and correct function of endothelial cells prevent platelet adhesion, activation of coagulation factors and formation of thrombi.
  • statins in reducing thrombotic risk and modulating plaque vulnerability were reported Libby P, Aikawa M, Clin Cardiol 2003;26(1 Suppl 1):I1 1- 114. Influence of statins on endothelial function and thrombotic risk was analyzed (Rosenson RS, Am J Cardiovasc Drugs 2001 ;1(6):41 1-20) and in W09513063 HMG- CoA reductase inhibitors were proposed for the normalization of vascular endothelial dysfunction.
  • statins influence the formation of arterial and venous thrombi (Alfon J et al, Thromb Haemost 1999;81 :822-827; Obi C et al, Arterioscler Thromb Vase Biol 2009;29(9): 1271 -1276) and blood coagulation (Owens AP et al, J Clin Invest 2012;122:558-568; Ramcharan AS et al, J Thromb Haemost 2009;7(4):514-520).
  • Statins are regarded as beneficial both at arterial and venous thrombosis (Lijfering WM et al, Semin Thromb Hemost 201 1 ;37:885-896).
  • the beneficial effect of statins on venous thrombosis and thromboembolism attracted serious attention in clinical research (Ray JG et al, Arch Intern Med 2001 ; 161 (1 1): 1405-10; Glynn RJ et al, N Engl J Med2009;360(18): 1851-1861 ; Khemasuwan D et al, Am J Med 201 1 ;124(9):852-859); Paraskevas KI et al, Current Medical Research and Opinion 2009;25(7): 1807-1809; Lacut K et al, Fundam Clin Pharmacol 2004; 18:477-82; Undas A et al, Arterioscler Thromb Vase Biol 2005;25:287-94), unfortunately not fully supported by the later meta-analysis of
  • statins amplify the anti-aggregant action of aspirin (Luzak B et al, Eur J Clin Invest, 2012;42:864-72). Treatment with statins can lead to a significant downregulation of the blood coagulation cascade (Szcezklik A et al, Med Sci Monit 2001 ;7(6): 1381-5. Undas A, Brummel-Ziedins KE, Mann KG, Arterioscler Thromb Vase Biol 2005;25(2):2878-94. Epub 2004, Nov 29).
  • US 6,235,31 1 disclosed a combination of aspirin and statin for reducing the risk of myocardial infarction.
  • WO2009022821 and WO2012081905 disclosed a combination preparation comprising inhibitor of HMG-CoA reductase and aspirin for treating cardiovascular conditions.
  • US 7,598,233 disclosed a pharmaceutical formulation comprising HMG-CoA reductase inhibitor and aspirin for treating thrombosis.
  • the aspirin salts with basic amino acids and glycine are combined with an inhibitor of HMG-CoA reductase.
  • Meldonium is an established cardiovascular agent with experimentally (Veveris M et al, Baltic J Lab Anim Sci 2002; 12(1 -2): 1 16-122. Artyushkova EV et al, Chelovek i ego zdorovye (in Russian) 2010;No.3:5-10. Vilskersts et al, Pharmacological Reports 201 1 ;63:752-762) and clinically established (Geichenko VP, Kuryata AV, Muzhchil OV, Rossiyskiy kardiologicheskiy zhurnal (in Russian) 2005; No.4:64-67.
  • Khlebodarov FE Mikhin VP, Gorlova AV, Rossiyskiy kardiologicheskiy zhurnal (in Russian) 2009;No.4:37-42.
  • Khlebodarov FE Turikov PYu, Mikhin VP Rossiyskiy kardiologicheskiy zhurnal (in Russian) 2009;No.6:34-40.
  • a combination of mildronate with statins was proposed in WO2006099244 for therapy of endothelial dysfunction, angina and diabetes, and in US201 10275649 for the preventing statin induced diabetes without any experimental data.
  • Meldonium acetylsalicylic acid addition salt is described in WO2010151095 as antiplatelet agent for treating various pathologies induced by platelet aggregation, as anti-inflammatory and antihyperlipidemic agent.
  • meldonium acetylsalicylic acid addition salt is described as coagulant factor XII inhibitor and combination thereof with warfarin as anticoagulant agent.
  • Providing a novel synergistic combination of antiplatelet agent and HMG-CoA reductase inhibitor statin can substantially reduce the risk or thrombosis.
  • the present invention provides an anti-thrombosis agent for treating thrombosis, comprising meldonium acetylsalicylic acid addition salt in combination with a statin.
  • a synergistic therapeutic combination for preventing and treating thrombotic conditions comprising therapeutically effective amount of meldonium acetylsalicylic acid addition salt as corrector of endothelial dysfunction and therapeutically effective amount of statin as HMG-CoA reductase inhibitor is described.
  • the animals were randomized into the following groups: a) intact animals group - received water; b) experimental endothelial dysfunction group - animals received once daily i.p. inhibitor of NO synthase L-NAME in 25 mg/kg dose and p.o. water according to protocol, c) treated experimental endothelial dysfunction group - the animals received L-NAME and test substance.
  • the experiment was conducted according to two protocols: 1) prophylactic and 2) therapeutic. l)According to prophylactic experimental protocol the preventing group animals besides L-NAME received once daily for 7 days via canula into stomach the test substance, the intact and L-NAME groups - water. 2) According to treatment protocol, the test substance was administrated on the background of developed endothelial dysfunction - starting with Day 5 of the experiment - immediately after the administration of L-NAME on Days 5, 6 and 7 the test substance or water (for intact group or L-NAME group) was administrated p.o..
  • acetylcholine Ach
  • NP sodium nitroprusside
  • EDF endothelial dysfunction factor
  • MASA in 5 mg/kg/d dose caused an effect on EDF changes superior to that caused by MD in dose 100 mg/kg/d (EDF 3.22 and 3.99, Table 2).
  • EDF 3.22 and 3.99, Table 2 EDF 3.22 and 3.99, Table 2.
  • MASA was unique in its effect to reduce the manifestation of endothelial dysfunction in treatment mode (see the influence on EDF and endothelium-dependent vascular reaction to Ach essentially similar to that of intact group, Table 2).
  • Such MASA effect would be a benefit in clinical use for treating endothelial dysfunction and restoring of endothelium function.
  • endothelium cells The functional state of endothelium cells is one of the main factors in providing for normal blood rheology and developing or preventing thrombosis. Therefore endothelial dysfunction considerably aggravates heart and vascular conditions with increased risk of thrombosis (Lowenberg EC et al, The Netherland J of Medicine 2010;68(6):242-250).
  • mice Male Wistar rats weighing 340-400 g were used. The animals were randomized into two parallel groups: 1) without endothelial dysfunction, 2) with endothelial dysfunction. Animals with endothelial dysfunction were treated by L- NAME (25 mg/kg/d i.p.) for 7 days; the intact animals received similar volume of sterile 0.9% NaCl solution. According to protocol, starting with Day 5 for 3 days animals received p.o. either the test substance or water immediately after administration of L-NAME or NaCl solution.
  • L- NAME 25 mg/kg/d i.p.
  • the thrombosis time was recorded as time when the blood flow was totally stopped and represented as time to occlusion (TTO).
  • TTO time to occlusion
  • the results were analyzed by Microsoft Excel 2007 program. Data are represented were expressed as mean ⁇ mean standard error (Mean ⁇ SEM) for 7-8 animals. Differences between different experimental groups were compared using one-way ANOVA with repeated comparisons (Tukey's test). P ⁇ 0.05 was considered as significant.
  • MASA significantly reduced endothelial dysfunction induced by experimental lowering of NO level when administrated both in preventive and therapeutic mode. When administrated therapeutically on the background of endothelial dysfunction, MASA more efficiently than MD or ASA reduced endothelial dysfunction and risk of vascular thrombosis.
  • MD or ASA reduced endothelial dysfunction and risk of vascular thrombosis.
  • a modified ferric chloride caused experimental thrombosis model in rats was used (Kurz K et al, Thromb Res 1990,60:269-280; Wang X, Xu L, Thromb Res 2005;115:95-100. Optimization of ferric chloride induced thrombosis model in rats: J Pharm Toxicol Methods 2010;61 :287-291).
  • the animals were randomized in groups of 10 and received once daily for 3 consecutive days water (control group) or the following substances were administrated p.o.: MASA 15 (15 mg/kg x 3), MASA 30 (30 mg/kg x 3), MD (25 mg/kg x 3), ASA (5 mg/kg x 3), MD + ASA (25+5 mg/kg x 3) or simvastatin (5 mg/kg x 3). Also the combinations of experimental substances with simvastatin were administrated p.o.
  • Rats were anaesthetized with pentobarbital sodium (50 mg/kg, i.p. and 10 mg/kg/h) and were placed on a heat controlled operating table throughout the experiment to maintain a body temperature of 37 °C.
  • pentobarbital sodium 50 mg/kg, i.p. and 10 mg/kg/h
  • One of the carotid arteries was exposed by cervical incision, separated from the adherent tissue, vagus nerve, and a flow probe (electromagnetic blood flow meter MFV 1200, Nicon Kohden, Japan) was placed on the exposed segment of common carotid artery to record the blood flow.
  • thrombosis was induced by topically applying (in contact with the adventitial surface of vessel) two pieces (2x1 mm) of Whatman filter paper, soaked in 15% solution of FeCl 3 .
  • Thrombosis time of carotid artery was recorded as time taken for the complete cessation of the blood flow and has been reported as time till occlusion (TTO). If the blood flow did not cease within 90 min. in the drug treated groups TTO was reported as >90 min.
  • Data are represented as Mean ⁇ SEM. Differences between different experimental groups were compared using one-way ANOVA with repeated comparisons (Tukey's test) and a value of PO.05 was considered as significant.
  • MASA 15 (15 mg/kg x 3) caused significant increase of TTO that was better pronounced than effects of ASA, MD or simvastatin.
  • MASA in combination with simvastatin caused unexpected and surprising increase of antithrombotic effect: MASA 15 mg/kg +simvastatin 5 mg/kg prolonged the TTO for 25% compared with that of MASA 15 mg/kg, while MASA 30 mg/kg + simvastatin 5mg/kg prolonged the TTO for 31% compared with MASA 30 mg/kg.
  • a synergistic therapeutic combination comprising therapeutically effective amount of meldonium acetylsalicylic acid addition salt as corrector of endothelial dysfunction and therapeutically effective amount of HMG-CoA reductase inhibitor statin, for use in preventing and/or treating thrombosis.
  • statin is selected from the group of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and their pharmaceutically acceptable salts.
  • thrombosis is associated with acute coronary syndrome, myocardial infarction, unstable angina pectoris, hypertension, vasospasm, transient ischemic attack, atrial fibrillation, stroke, arteriosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, coronary arterial thrombosis, arterial embolism, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, diabetes, surgery and blood congestion.
  • a synergistic pharmaceutical composition comprising first therapeutic agent meldonium acetylsalicylic acid addition salt as corrector of endothelial dysfunction and second therapeutic agent HMG-CoA reductase inhibitor statin, for use in preventing and/or treating thrombosis.
  • statin is selected from the group of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and their pharmaceutically acceptable salts.
  • composition of claim 6 comprising meldonium acetylsalicylic acid addition salt and HMG-CoA reductase inhibitor as separate pharmaceutical formulations.
  • composition of claim 6 comprising meldonium acetylsalicylic acid addition salt and HMG-CoA reductase inhibitor as single pharmaceutical formulation.
  • composition of claim 6, wherein the thrombosis is associated with acute coronary syndrome, myocardial infarction, unstable angina pectoris, hypertension, vasospasm, transient ischemic attack, atrial fibrillation, transient ischemic attack, stroke, arteriosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, coronary arterial thrombosis, arterial embolism, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, diabetes, surgery and blood congestion.

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Abstract

La présente invention concerne une combinaison thérapeutique synergique comprenant un sel d'addition d'acide acétylsalicylique de meldonium, utilisée comme correcteur de la dysfonction endothéliale et inhibiteur de la HMG-CoA réductase dans la prévention et/ou le traitement de la thrombose.
PCT/LV2014/000006 2013-06-28 2014-06-27 Correcteur de dysfonction endothéliale WO2014209092A1 (fr)

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Application Number Priority Date Filing Date Title
LVP-13-88A LV14963B (lv) 2013-06-28 2013-06-28 Endoteliālās disfunkcijas korektors
LVP-13-88 2013-06-28

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WO2014209092A1 true WO2014209092A1 (fr) 2014-12-31

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Citations (16)

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