WO2010151096A1 - Therapeutic combinations of nicotinic acid and meldonium - Google Patents

Therapeutic combinations of nicotinic acid and meldonium Download PDF

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Publication number
WO2010151096A1
WO2010151096A1 PCT/LV2010/000008 LV2010000008W WO2010151096A1 WO 2010151096 A1 WO2010151096 A1 WO 2010151096A1 LV 2010000008 W LV2010000008 W LV 2010000008W WO 2010151096 A1 WO2010151096 A1 WO 2010151096A1
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pharmaceutically acceptable
combination
acceptable salt
group
release
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PCT/LV2010/000008
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English (en)
French (fr)
Inventor
Ivars Kalvins
Anatolijs Birmans
Maris Veveris
Antons Lebedevs
Anatolijs Misnovs
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Tetra, Sia
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Priority claimed from LVP-09-116A external-priority patent/LV14266B/lv
Application filed by Tetra, Sia filed Critical Tetra, Sia
Priority to CN201080027377.6A priority Critical patent/CN102802618B/zh
Priority to UAA201200602A priority patent/UA107083C2/ru
Priority to EA201200037A priority patent/EA021344B1/ru
Priority claimed from LVP-10-94A external-priority patent/LV14462B/lv
Publication of WO2010151096A1 publication Critical patent/WO2010151096A1/en

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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

  • Present invention relates to a combination medicinal product and method of prevention and/or treatment of metabolic-related disorders, including dyslipidemia, hyperlipidemia, atherosclerosis, coronary heart disease as chosen from the group of angina pectoris and myocardial infarction, transient and permanent ischemic attack including cerebrovascular accident and stroke and peripheral arterial occlusive disease, prevention of platelet aggregation and thrombosis.
  • metabolic-related disorders including dyslipidemia, hyperlipidemia, atherosclerosis, coronary heart disease as chosen from the group of angina pectoris and myocardial infarction, transient and permanent ischemic attack including cerebrovascular accident and stroke and peripheral arterial occlusive disease, prevention of platelet aggregation and thrombosis.
  • the invention relates to combination medicinal product containing nicotinic acid (niacin) and meldonium that synergistically enhances curing effects of nicotinic acid and ameliorates certain undesirable side effects of nicotinic acid, in particular peripheral vasodilatation (flushing) and elevations in blood glucose levels.
  • the invention also relates to a pharmaceutical composition comprising such combination medicinal product and to the use thereof in the manufacture of a medicament for prevention and/or treatment of metabolic-related disorder.
  • RPP - rate pressure product mean blood pressure x heart rate x IOOO 1
  • NA is important agent for treatment of dyslipidemias and the only agent currently available that favourably influences all components of lipid profile: lowers in blood the levels of total cholesterol, TG and LDL-C and has the most pronounced HDL-C raising activity among lipid-altering agents (Pieper JA, Am J Manag Care 2002;8(12 Suppl):S308-14).
  • NA in the treatment of dyslipidemias has been reported as early as 1955 (Altshul R, Hoffer A, Stephen JD, Arch Biochem Biophys 1955;54:558-559) and 1959 (Parsons Jr WB, Flinn JH, AMA Arch Intern Med 1959; 103:783-790). Since NA efficiently raises HDL-C levels (McKenney J, Arch Intern Med 2004;164(7):697-705. Carlson LA, J Intern Med 2005;258:94-114), NA is currently combined with other lipid-modifying agents that mostly act on LDL-C levels, in order to increase HDL-C levels (Rosenson RS, Am J Med 2005; 118(10): 1067-77).
  • NA is an effective lipid-altering agent that prevents atherosclerosis progression and reduces clinical cardiovascular events (Savel'ev AA, Shershevskii MG, Klin Med (Rus) 1996;74:48-52. Drexel H, European Heart Journal Supplements 2006;Vol 8, Suppl F: F23-F29. Brown BG, Zhao XQ, Am J Cardiol 2008;101(8A):58B-62B) by raising HDL-C levels. NA decreases morbidity and mortality rates in patients with hyperlipidemia (Canner PL et al, J Am Coll Cardiol 1986;8: 1245-55).
  • NA is the most effective agent at increasing HDL-C in treating hyperlipidemic cases (Ellingworth DR et al, Arch Intern Med 1994; 154: 1586-95. Schectman G et al, Am J Cardiol 1993;71:758-65). NA diminishes thrombosis, reduces blood viscosity and has cardioprotective effects that may limit ischemia- reperfusion injury. (Lamping KA et al, Pharm Exp Ther 1984;231(3):532-538. Trueblood NA et al, Am J Physiol Heart Circ Physiol 2000; 279(2), H764-H771. Rosenson RS Atherosclerosis 2003;171(l):87-96).
  • NA is available in 3 formulations (immediate release, extended release, and long acting). Immediate-release NA is associated with adverse flushing and elevations in blood glucose levels. Long-acting NA is associated with reduced flushing, but also with risk of hepatotoxic effects. Extended-release is associated with less flushing and low hepatotoxic risk (Pieper JA, Am J Health Syst Pharm 2003;60(13 Suppl 2):S9-14. McKenney J, Arch Intern Med 2004;164(7):697-705. Knopp RH, Am J Cardiol 2008;86(Suppl);51L-56L). The use of NA sodium, potassium and magnesium salts is also described.
  • NA A major shortcoming of NA is the necessity of administering large doses to substantially alter blood lipid levels. Almost 100% of subjects treated with NA experience unpleasant side effects of flushing that in many cases prevent the therapy with NA. Cutaneous release of prostaglandin D2 was identified as the immediate cause of NA-induced flushing (Morrow JD et al, J Invest Dermatol 1992;98:812-5). Since NA-related flushing is a result of prostaglandin activity, acetylsalicylic acid as a well-established inhibitor of prostaglandin synthesis was proposed and is used to control the flushing.
  • NSAIDS Besides acetylsalicylic acid other NSAIDS are also active (Oberwittler H, Baccara-Dinet M, Int J Clin Pr ⁇ ct 2006;60(6):707-715). However NSAIDS are not devoid of side effects themselves and can cause gastrointestinal irritation and ulceration.
  • niacin with laropiprant may therefore enable use of niacin at higher doses and therefore exploit the full potential of the drug (Parhofer KG, Vascular Health and Risk Management 2009;5:901-908, Olsson AG, Expert Opinion on Pharmacotherapy 2010;l l(10):1715- 1726).
  • Type 2 diabetes Patients with Type 2 diabetes often have dyslipidemic changes characterized by an increase in TG levels as well as a decrease in HDL-C levels. Considering the pharmacological effects of NA on lipid metabolism, NA should counteract the dyslipidemic changes in patients with Type 2 diabetes.
  • NA increases insulin resistance (Garg A, Grundy SM, JAMA 1990;264: 723-6. Kahn SE et al, Diabetes 1989;38:562-8) and rises glucose levels (Elam, MB et al, JAMA 2000;284( 10): 1263- 1270). Therefore only limited doses of NA ( ⁇ 2 g/day) are recommended for diabetic patients.
  • NA is an effective lipid-altering agent that prevents atherosclerosis and reduces cardiovascular events.
  • NA has multifarious lipoprotein and anti-atherothrombosis effects that improve endothelial function, reduce inflammation, increase plaque stability, and diminish thrombosis (Rosenson RS, Atherosclerosis 2003; 171 :87-96)
  • NA inhibit platelet aggregation (Lakin KM, Farmakol Toksikol, 1980; 43(5):581-5). NA in vitro affects platelet activity by mildly inhibiting aggregation, and stimulating significant prostaglandin release, with mostly intact major platelet receptor expression. The effect of NA is unique, differs from other known antiplatelet agents, and suggests potential opportunities for therapeutic combination (Serebruany VL et al, Thrombosis and Haemostasis, 2010 (in press).
  • NA almost totally prevented intravascular clotting induced by thromboplastin and pituitrin, showing that it has a thrombolytic effect (Baluda VP, Kardiologija 1974; 14(11): 105-7 (Rus). Anti-thrombotic properties of NA are described by several authors (Shestakov VA, Probl Gematol Pereliv Krovi, 1977;22(8):29-35. Chekalina SI, Sov Med 1982(5): 105-8). Niacin reduces risk of blood clots (Chesney CM et al, Am Heart J, 2000;140:631-36).
  • MD is a medicine with certain beneficial effects on heart and vessels.
  • a certain desirable activity of MD was discovered in animal models of atherosclerosis (Veveris M, Smilsaraja B, Baltic J Lab Anim Sci 2000; 10, 194- 199. Veveris M et al., Baltic J Lab Anim Sci 2002;12:l 16-122.
  • Koreanpov RS et al, Ter Arkh 1991;63(4):90-3 were observed in clinics.
  • combination therapy may offer particularly desirable benefits in patients as compared with monotherapy. Since progress in developing new agents for lowering LDL-C levels has slowed down, the research has turned to developing better agents for raising HDL-C levels. There has been increasing use of combination therapy comprising NA, fibrates, statins and bile acid sequestrants for the treatment of metabolic-related disorders, due to the additive profiles of combined products (Miller M, Mayo Clin Proc 2003;78(6):735-42.
  • the combination medicinal product of the present invention is anticipated to have a synergistic effect in a method for treatment and/or prevention of metabolic-related disorders, including dyslipidemia, hyperlipidemia, atherosclerosis, coronary heart disease as chosen from the group of angina pectoris and myocardial infarction, transient and permanent ischemic attack including cerebrovascular accident and stroke and peripheral arterial occlusive disease, preventing platelet aggregation ant thrombosis.
  • a combination medicinal product is defined as having a synergistic effect if the effect is therapeutically superior to that of NA or MD separately.
  • a combination pharmaceutical product as used herein means simultaneous, sequential or separate administration of the agents of the combination.
  • An additional object of the invention is the provision of a pharmaceutical composition comprising both NA and MD for the aforesaid purpose. Further objects of the invention will become apparent hereinafter, and still others will be obvious to one skilled in the art. DESCRIPTION OF THE INVENTION
  • the invention comprises the combination of NA and MD with the result that an effective synergistic combination for treating metabolic-related disorders is provided, preferably in a single-dosage unit form.
  • the two ingredients may be administered separately simultaneously or sequentially in any order.
  • the exact form in which the active ingredients are administered is not important, so long as the desired effect of the invention is obtained.
  • the active ingredients may take the form of capsules, suspensions, dispersions, elixirs, syrups, or the like, whether administered separately or in single composition.
  • NA and MD have synergistic action on metabolic-related disorders and other beneficial effects. It was unexpectedly discovered that MD is the first agent that enhances the beneficial effects of NA, namely lowering the TG and LDL-C levels and increasing the HDL-C levels, enhances the antiaggregating effect of NA and ameliorates the undesirable side effects of NA, in particular flushing and elevations in blood glucose levels.
  • said combination is anticipated to be a preferable agent for treating dyslipidemia in patients with diabetes.
  • the combination of present invention ameliorates the aftereffects of experimental infarction and stroke.
  • NA and MD have synergistic action on platelet aggregation. It was unexpectedly discovered that MD is the first agent that enhances the antiplatelet effects of NA.
  • the combination of the invention may be in a form suitable for oral use (for example as tablets, capsules, aqueous suspensions or dispersible powders or granules), for parenteral administration (for example as a sterile aqueous solution for intravenous, subcutaneous, or intramuscular dosing) or as a suppository for rectal dosing.
  • the composition of the invention is in a form suitable for oral use, for example as tablets or capsules.
  • a combination product according to the present invention also includes combination of separate pharmaceutical compositions of active agents comprising a first composition of NA or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier, and a second composition comprising MD or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.
  • Such a combination of pharmaceutical compositions provides the combination medicinal product of the invention for simultaneous or sequential use. The advantage of such combination is in the possibility for the physician to adjust the proportion of active agents for the individual patient.
  • the combination medicinal product of the present invention is anticipated to include also sustained-release and extended release formulations of NA, as well as pharmaceutically acceptable salts of NA (sodium, potassium or magnesium) and MD and salts thereof.
  • the combination medicinal product of the present invention can also include other medicinal products with known activity in metabolic-related disorders, namely statins, in particular, Simvastatin.
  • the combination medicinal product of the present invention can also include other medicinal products with known activity in metabolic-related disorders, namely inhibitors of platelet aggregation, in particular, clopidogrel or dipyridamole.
  • composition of the invention may be obtained by conventional procedures using conventional pharmaceutically acceptable excipients or carriers and technologies.
  • the following examples are provided to illustrate but not limit the invention.
  • Tests The pharmacological activity of tested substances was investigated by standard methods used in the art. Animals were kept in groups of 6 in adequate cages in climatized rooms at 22 ⁇ 1 0 C, relative humidity 60 ⁇ 5% and 12/12 light/darkness cycle with free access to feed and water. All experiments were carried out in accordance with the European Community Council's Directive of 24 November 1986 (86/609/EEC) relative to experimental animal care. All efforts were made to minimize animal suffering and to reduce the number of animals used.
  • Total C, HDL-C, LDL-C and TG in serum were determined by commercial test kits.
  • LDL-C/HDL-C ratio is accepted as standard tool to evaluate cardiovascular risk (Fernandez ML, Webb D, JAm Coll Nutr, 2008;27(l):l-5).
  • the combination of NA and MD exhibits statistically significant effect on lowering LDL-C and TG levels and increasing the HDL-C levels.
  • the summary effect was surprisingly higher than the effect of each substance alone. It is particularly evident in atherosclerotic index and total C/HDL-C rate, where a synergy of NA and MD effects is observable.
  • NA5O+MD5O NA 50 mg/kg + MD 50 mg/kg
  • NA50+MD150 NA 50 mg/kg + MD 150 mg/kg
  • NA200+MD200 NA 200 mg/kg + MD 200 mg/kg ⁇ P ⁇ 005 vs C control **P ⁇ 0 005 vs C control *P ⁇ 00005 vs C control sP ⁇ 005 vs NA in same dose *P ⁇ 005 vs MD in same dose
  • the anti-atherosclerotic activity of the combination of present invention was evaluated in more detail, and further also the known anti-lipidemic agent, SI was added to the combination.
  • NA and MD when used separately, displayed a tendency to decrease the area of damage (Table 3).
  • the combination of NA+MD caused considerably higher and statistically significant protective effect against the atherosclerotic damage than each substance separately.
  • Adding of the combination of the present invention to SI further increased its protective activity against atherosclerotic damage.
  • NA 50 +MDl 5 0 NA 5 0 mg/kg + MD I 50 mg/kg
  • NA 50 +MD 5 O+S110 NA 5 0 mg/kg + MD 5 0 mg/kg + SI lO mg/kg
  • NAMg and NA+SI combination were included in the comparative evaluation (Table 5).
  • NAMg had been compared with NA in cockerels (Burstein J, Telkka A, Acta Pathol Microbiol Scand 1962;56:261-265).
  • the combination of NA (50 mg/kg) and MD (150 mg/kg) had the most pronounced beneficial effect against aorta, better than NA and NAMg, as well as surpassing that of SI and NA combination, used in rate based on clinical experience (Pandian A et al, Vase Health Risk Manag 2008;4(5): 1001-1009).
  • NA50+MD150 NA 50 mg/kg + MD 150 mg/kg
  • NA50+SI2 NA 50 mg/kg +SI 2 mg/kg *P ⁇ 005 vi C control **P ⁇ 0 005 vs C control ***P ⁇ 0 0005 vs C control $P ⁇ 0 05 VJ NA @ P ⁇ 0 05 vs NAMg 4P ⁇ 005 vs MD *P ⁇ 005 vs NA50+SI2
  • NA50+MD150 NA 50 mg/kg + MD 150 mg/kg
  • NA50+SI2 NA 50 mg/kg +Sl 2 mg/kg *P ⁇ 005 vs C control **P ⁇ 0 005 vs C control ***P ⁇ 0 0005 vs C Control sP ⁇ 005 ra NA @P ⁇ 005 vs NAMg *P ⁇ 005 vs MD
  • NA+MD is similar to combination of NA+SI in lowering total C and LDL-C, but substantially surpass it in influence on beneficial effect on HDL-C and TG levels, as well as has more pronounced effect on atherosclerotic index and total C/HDL-C rate.
  • Example 2 Influence of NA and MD, separately and in combination on lipids in rat hvperlipidemia model
  • NA+MD Triton 250 mg/kg + NA 50+MD 150 mg/kg/d
  • NA+SI2+MD (TR 250 mg/kg + SI 2 + NA 50 + MD 150 mg/kg/d) 12 Blood for biochemical analyses was obtained after 1 , 2 and 3 weeks (on the next day after TR injection) by cardiac punction under ether narcosis. Serum was separated by centrifugation and analyzed for total C, HDL-C, LDL-C and TG levels by commercial kits. Statistics. The data obtained were mathematically processed using Microsoft Excel program and the results were expressed as mean ⁇ standard error of the mean (SEM). Mean results of different groups were compared using one-way ANOVA and Student's t-test. Difference of the results were considered significant at P ⁇ 0.05. Results.
  • NA+MD is expected to be useful in clinic for preventing and/or treating hypercholesterolemia and hyperlipidemia.
  • Control group received p.o. 0.9% saline
  • NA50 group received p.o. 50 mg/kg/day of NA
  • MD50 group received p.o. 50 mg/kg/day of MD;
  • NA50+MD50 group received p.o. 50 mg/kg/day NA plus 50 mg/kg MD;
  • MD 150 group received p.o. 150 mg/kg/day of MD;
  • NA50+MD150 group received p.o. 50 mg/kg/day of NA plus 150 mg/kg/day of MD.
  • Necrotic index Necrotic zone/Ischemic zone x 100
  • Example 4 Determination of antihypoxic and antiishemic effects on brain Further experiments were conducted to determine the effect of NA and MD combination medicinal product in experimental CNS ischemia, hypoxia and stroke models in comparison with effects of separate components.
  • Control group received water 0.01 mL/g
  • PI500 group (active control) received 500 mg/kg dose of piracetam
  • NA50 group received 50 mg/kg dose of NA
  • MD50 group received 50 mg /kg dose of MD
  • MDl 50 group received 150 mg/kg dose of MD
  • NA50+MD50 group received a dose of 50 mg/kg NA plus 50 mg/kg MD
  • NA50+MD150 group received a dose of 50 mg/kg NA plus 150 mg/kg MD
  • the last dose of test substance was given 1 hour before the test.
  • the period between the end of the MgCl 2 injection and the cessation of the last respiratory movements was registered as survival time.
  • MCA Middle cerebral artery
  • brains were isolated and sliced in 6 layers of about 1.5 mm thickness. Slices were stained with 2% triphenyltetrazolium sodium at 37 0 C for 30 min. and photographed. As the most adequate for calculating the brain ischemic damage the 3rd slice from cranial side on the chiazma opticum level was selected, since it was completely supplied by blood from the middle cerebral artery.
  • the combination of NA plus MD provides a significantly better protection against functional and morphological damage of brain tissue than separate components when used therapeutically either before or after the occlusion of MCA.
  • the combination medicinal product may be beneficial in treating and/or preventing CNS ischemic-hypoxic conditions including stroke, also due to its inhibiting activity in platelet aggregation and thrombosis tests, as outlined below.
  • Tests Platelet aggregation in vitro; rat thrombosis model in vivo; registration of changes in skin temperature in vivo were performed.
  • Platelet aggregation was studied in whole blood obtained from healthy donor B. (37 y. old) who did not use ASA or other antiplatelet agents, using Multiplate (Multiple Platelet Function Analyzer, Dynabyte Medical, Germany) with established method (Toth O et al, Thromb Haemost, 2006;96:781-788. Velik-Salchner C et al, Anesth Analg 2008;107:1798-1806). Blood samples were collected into plastic tubes covered with hirudin (Dynabyte Medical, Germany) and used for measurement between 30 min and 4 h after collection. The measurements were performed according to modified Dynabyte Medical protocol.
  • Isotonic sodium chloride solution (0.3 ml, or saline with test substance (in final concentration 10 "6 to 10 "4 mmol/ml)) was pre-heated to 37 0 C, pipetted into the test cells and 0.3 ml of whole blood sample anticoagulated with hirudin was added. After 5 min incubation and stirring at 37 C, measurements were initiated by adding of the appropriate agonist solution (sourced from Dynabyte Medical, Germany): 1) adenosine diphosphate (ADP) - ADP-Test. ADP stimulates platelet activation by the ADP receptors (P2Y12 and other). 2) ADP HS test (prostaglandin Ei in combination with ADP). The addition of the endogenous inhibitor PGEi makes ADP HS test more sensitive compared to ADP test. Aggregation curves were recorded for 6 min and analyzed using Dynabyte Medical software. We calculated the following parameters of platelet aggregation:
  • Amax the maximal value of platelet aggregation expressed in arbitrary units (AU) of aggregation
  • AUC total area under the aggregation curve (AU*min). It is affected by the total height of the aggregation curve as well as by its slope and is best suited to express the overall platelet activity.
  • Rats were anaesthetized with pentobarbital sodium 50 mg/kg, Lp. and were placed on a heat controlled operating table throughout the experiment to maintain a body temperature at 37 0 C.
  • 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. After a stabilization period of 15 min, 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).
  • TTO time till occlusion
  • rat tail bleeding time was measured.
  • the tail was transected 5 mm from the tip with scalpel and the tail was immediately immersed into 37 0 C warm isotonic saline until termination of bleeding was noted. Termination of bleeding was defined as the time of complete stop of bleeding with no recurrence of bleeding within the next 30 s.
  • Nicotinic acid (niacin, NA) effectively lowers serum cholesterol, LDL and triglycerides, while raising HDL.
  • a limiting adverse effect in patients receiving immediate-or sustained-release niacin is the rapid development of significant cutaneous warmth and vasodilatation, referred to as "flush" which severely leading to discontinuation (Gupta EK, Ito MK, Heart Dis 2002;4: 124-137).
  • Laropiprant (MK-0524) has been proposed as one of the most active and perspective agent for reducing niacin flushing (Cheng K et al, PNAS 2006; 103:6682-6687). The objective of our investigation was comparing the effect of MD and LA on flushing (changes of skin temperature and blood flow) caused by NA in experiment.
  • Results were calculated from 5 to 8 separate experiments and expressed in % as maximal change in blood flow to baseline [Carballo-Jane E et al, J Pharmacol Toxicol Methods 2007;56(3): 308-316].
  • Statistics The results are presented as means ⁇ SEM for each group. Statistical analysis within groups was performed by Student t-Test for unpaired data and Chi- square Test. Differences between each experimental group were compared using oneway ANOVA with repeated comparisons (Tukey's test). P ⁇ 0.05 was considered as significant.
  • LA+NA [30] LA 0.3 mg/kg+NA 15 mg/kg 7
  • NA+MD [30] NA 15 mg/kg+MD 45 mg/kg 6
  • LA was introduced simultaneously with NA as NA+LA [0] or 30 min in advance of NA as NA+LA [30]
  • MD was introduced simultaneously with NA as NA+MD [0] or 30 min in advance of NA as NA+MD [30]; also the effects of LA and MD alone on skin temperature were checked.
  • the baseline mean ear temperature was 28.1-30.2 0 C recorded at 10 AM to 2 PM.
  • a time response study for NA (15 mg/kg s.c.) showed a maximal temperature increase of 2.32 ⁇ 0.37 0 C from baseline and 2.57 ⁇ 0.43 in comparison with Solvent group (PO.005) at 10 min (below). It was established that the effect of the LA solvent on ear temperature was substantially different from that of NA and MD solvent only in the first 5 min after injection, therefore only one control group was used.
  • SoIvLA Subcutaneous injection of MD or LA did not cause significant changes in rat ear skin temperature (Table 21).
  • the increase of temperature, caused by NA was reduced, correspondingly, to 69% and 67 % (Table 21).
  • There was no significant difference on temperature between the MD+NA [0] when MD was added together with NA
  • MD+NA [30] pretreatment 30 min in advance with MD 45 mg/kg.
  • pre-treatment with LA when given s. c. at dose 0.3 mg/kg 30 min before the injection of NA, caused significant protection against the increase of skin temperature, induced by NA (Table 21).
  • Control group (received 1 % NaCl solution, dose 2 ml/kg)
  • NA+MD group (received 300 mg/kg NA and 300 mg/kg MD).
  • NA and MD enhanced the curative effect of NA on disorders, including dyslipidemia, hyperlipidemia, atherosclerosis, coronary heart disease as chosen from the group of angina pectoris and myocardial infarction, transient and permanent ischemic attack including cerebrovascular accident and stroke and peripheral arterial occlusive disease, improved the condition of heart and brain under ischemic-hypoxic conditions.
  • the combination also ameliorated the peripheral vasodilatation caused by NA. Therefore the novel combination medicinal product is expected to exhibit improved activity compared to NA in treating metabolic-related disturbances, allowing to reduce daily doses of NA, and have less pronounced undesirable side effects.
  • a combination medicinal product used herein provides for the simultaneous, sequential or separate administration of the components of the combination.
  • a combination medicinal product comprising NA and MD or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately for the prevention of platelet aggregration.
  • a combination medicinal product of the invention may be administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition which comprises NA or a pharmaceutically acceptable salt thereof and MD or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition according to the present invention also includes separate compositions comprising a first composition of NA or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, and a second composition comprising MD or pharmaceutically acceptable salt thereof and a pharmaceutically-acceptable diluent or carrier.
  • Such a composition provides for sequential or separate use. Since the treatment or prevention of metabolic-related disorders presumes prolonged use of medicinal product, the most preferable mode of carrying out the invention is provided by a form suitable for oral use, for example as tablets or capsules.
  • the amount of each active ingredient of the present combination medicinal product in a pharmaceutical composition will vary depending upon the condition treated. Those skilled in the art of treating metabolic-related disorders patients can readily select the appropriate amounts of each active ingredient and a suitable dosing schedule.
  • the preferable ratio of the active ingredients NA and MD or salt thereof is from 3:1 to 1:3.

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CN104161769B (zh) * 2014-08-16 2016-01-20 广州一品红制药有限公司 一种含环磷腺苷的组合物及其应用
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CN104622882B (zh) * 2015-01-12 2017-12-05 青岛市中心医院 用于治疗动脉粥样硬化的药物组合物及其用途

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012158003A1 (en) * 2011-05-17 2012-11-22 Tetra, Sia Novel factor xii inhibitor
WO2014209092A1 (en) * 2013-06-28 2014-12-31 Tetra, Sia Corrector of endothelial dysfunction

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