LV14462B - A combination medicinal product for inhibition of platelet aggregation - Google Patents

Abstract

A synergistic combination medicinal product having increased activity in prophylaxis of platelet aggregation and/or thrombi formation, consisting of an effective amount of nicotinic acid or pharmaceutically acceptable salt thereof and an effective amount of meldonium or pharmaceutically acceptable salt thereof.

Description

DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION

The present invention relates to a combined medical product and to a method for preventing and / or treating platelet adhesion.

More particularly, the present invention relates to a combined medical product comprising nicotinic acid (niacin) and meldonia, which synergistically enhance the therapeutic effects of nicotinic acid. The present invention also relates to a pharmaceutical composition comprising such a combination medical product and its use in the manufacture of a medicament for the prevention and / or treatment of platelet adhesion and thrombotic disorders.

ABBREVIATIONS USED

For the sake of brevity, the following abbreviations will be used in the description below:

ADF - adenosine diphosphate ASS - acetylsalicylic acid LA - laropiprant MD - meldonium (SNN)

NS - nicotinic acid PGEj - prostaglandin Εχ

FIELD OF THE INVENTION

Platelets play an important role in the development of atherosclerosis and the formation of fatal thrombi in coronary heart disease. Antiplatelet agents have become very important in the prevention and treatment of various diseases, including various cardiovascular, cerebrovascular and peripheral arterial diseases (Meadows TA et al, Circ Res 2007; 100 (9): 1261-75). NS is an effective lipid-sparing agent that prevents atherosclerosis and reduces the likelihood of cardiovascular events. NS has diverse effects on lipoproteins and arterial thrombosis, improving endothelial function, reducing inflammation, increasing plaque stability and reducing thrombus formation (Rosenson RS, Atherosclerosis 2003; 171: 87-96).

NS almost completely prevents the formation of clots in the blood vessels caused by thromboplastin and pituitrin, suggesting its thrombolytic activity (Baluda VP, Cardiology 1974; 14 (11): 105-7 (Rus). The properties of NS anticoagulants have been described by several authors (Shestakov VA, Probl Gematol Pereliv Krovi, 1977; 22 (8): 29-35. Chekalina SI, Sov Med 1982 (5): 105-8) NS reduces blood clot formation (Chesney CM et al, Am Heart J, 2000; 140: 631-36).

NS inhibits platelet adhesion (Lakin KM, Farmakol Toksikol, 1980; 43 (5): 581-5). NS affects platelet activity in vitro, slightly inhibiting adhesion and promoting the release of significant prostaglandins, essentially without affecting the expression of major platelet receptors. The effect of NS is unique, unlike other anti-caking agents, indicating the potential for its use in combination therapy (Serebruany VL et al., Thrombosis and Haemostasis, 2010 (in press).

MD has also been reported to inhibit platelet aggregation (TsirkinVI, Ros Kardiol Zh 2002; 1: 45-52). Oral use of MD for two weeks in experimental arterial thrombosis therapy in rabbits and dogs has shown thrombolytic effects (Logunova L et al., Experim Clin Pharmacoter 1991; 19: 91-98 (Rus). No data are available on the prophylactic effect of MD on thrombosis control or prevention.

The clinical application of NS was limited by skin redness. Slow-release nicotinic acid may help in the control of redness (Guyton JR et al., J Clin Lipidol, 2009; 3: 101-108). Recently, a specific prostaglandin D2 receptor subtype I antagonist laropiprant has been proposed to limit NS-induced redness (Lai E et al, Clin Pharm Ther 2007; 81: 849-857. Davidson MH, AmJCardiol 2008; 101 [suppl]: 14B-19B). , Vascular Health and Risk Management 2009; 5: 901-908). Although the use of laropiprant reduces the incidence of redness, it cannot completely eliminate this side effect. Laropiprant does not alter the effects of nicotinic acid on lipids, nor does it alter the other side effects of nicotinic acid. Therefore, the combination of nicotinic acid and laropiprant may allow the use of higher doses of nicotinic acid and the full potential of this agent (Parhofer KG, Vascular Health and Risk Management 2009; 5: 901-908, Olsson AG, Expert Opinion on Pharmacotherapy 2010; 11 (10): 17151726). .

TECHNICAL LEVEL

The current trend towards combined medical products for the treatment of cardiovascular disorders may improve the effectiveness of clinical care [Black DM, Curr Ther Rep 2003; 5: 39-32]. Increased use of combined drugs containing NS and other substances such as acetylsalicylic acid and other NSAIDs to inhibit platelet adhesion (US 5,981,555). However, these combinations do not increase relatively weak NS antiplatelet activity, i.e. no synergy has been reported. Therefore, new agents that could enhance the therapeutic effects of NS in the treatment of cardiovascular disease without enhancing the adverse effects of NS would have a beneficial effect in the clinic.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a combined medical product for the prevention of platelet adhesion and thrombosis and a method for preventing the occurrence of platelet adhesion and thrombosis in an individual in need thereof using NS in combination with MD. The medical product of the present invention is expected to have a synergistic effect in the antiplatelet and thrombosis prevention methodology.

According to the present invention, a combination medical product is defined as having a synergistic effect when its effect is therapeutically superior to that of a single agent NS or MD. It is understood that the term combined pharmaceutical product as used herein refers to the simultaneous, sequential or separate administration of combination agents. A further object of the present invention is a pharmaceutical composition comprising NS and MD for the above purpose. Other objects of this invention will become apparent later, and others will be apparent to the skilled artisan.

DESCRIPTION A comprises a combination of NS and MD that form an effective synergistic anti-adherent anti-adhesive agent, preferably in a single dose form, the components may be administered alone or sequentially in any order in which the active ingredients are administered, unless the effect of the invention is present. The active ingredients may be in the form of capsules, suspensions, ointments, syrups or the like, whether or not they are formulated in a short formulation.

n unexpectedly found that NS and MD act synergistically on platelet dit, MD was found to be the first agent to enhance the prevention of NS ocyte adherence.

this combination is expected to be an option in patients at risk of platelet change.

The combination described herein may be in the form of tablets, capsules, aqueous suspensions or dispersible powders for oral use. also in a form suitable for parenteral administration (such as sterile intravenous, subcutaneous or intramuscular administration) or as an administration. The preferred combination of the invention is in the form of an oral brush, such as tablets or capsules.

The product of the present invention also comprises a combination of an active pharmaceutical composition, wherein the first composition comprises an ice-acceptable salt and a pharmaceutically acceptable adjuvant, or the composition comprises MD or a pharmaceutically acceptable salt thereof and a adjuvant or carrier. Such a pharmaceutical composition is provided for the uniform or sequential use of the combination medical product described in the invention. The advantage of this combination is the ability for the physician to adjust the active ingredient ratio to the individual patient. It is contemplated that the combination medical product described in the invention will also include NS sustained release and sustained release dosage forms as well as pharmaceutically acceptable

NS salts (sodium, potassium or magnesium) and MD and its salts.

The pharmaceutical composition of the invention may be prepared by conventional procedures using conventional pharmaceutically acceptable excipients or carriers and technologies.

The following examples illustrate but do not limit the invention.

EXAMPLES

Tests: In vitro platelet adhesion assay, rat thrombosis model in vivo; recorded changes in skin temperature in vivo.

The pharmacological activity of the test compounds was investigated by standard methods used in the art. The animals were housed in groups of 5-8 in appropriate cages in air-conditioned rooms with a temperature of 22 ± 1 ° C, a relative humidity of 60 ± 5% and a 12/12 hour light / dark cycle, free access to water and food (R70 Lactamin, Sweden). All experiments were carried out in accordance with Council Directive 86/609 / EEC of 24 November 1986 on the use of animals for scientific purposes. Every effort was made to minimize animal suffering and reduce the number of animals used.

Substance: NS (Acros Chemicals), MD (Grindex), ASS (Acros Chemicals), LA (MK 0524, Cayman Chemicals). All other chemicals are obtained from commercial sources.

Example 1. Effect of MD and NS on platelet adhesion

The method. Platelet adherence was studied using whole blood obtained from healthy donor B. (37 years) who had not used ASA or other antiplatelet agents, with a Multiplate (Multiple Platelet Function Analyzer, Dynabyte Medical, Germany) according to a recognized method (Toth 0 et al., Thromb Haemost 2006; 96: 781-788. Velik-Salchner C et al., Anesth Analg 2008; 107: 1798-1806). Blood samples were collected in plastic hirudin-coated tubes (Dynabyte Medical, Germany) and used for measurements within 30 min. up to 4 hours after collection. Measurements were performed according to a modified Dynabyte Medical protocol. Isotonic sodium chloride solution (0.3 ml or saline together with test substance (concentration 10 ' ⁶ - 10' ⁴ mmol / ml) was warmed to 37 ° C and pipetted into measuring cells by adding 0.3 ml whole blood sample to hirudin added as anticoagulant After 5 minutes of incubation and mixing at 37 ° C, a solution of the appropriate agonist (from Dynabyte Medical, Germany) was added to start the process: 1) adenosine diphosphate (ADF) - ADF test. ADF stimulates platelet activation by ADF receptors (Ρ2Υ12, etc.). 2) ADF HS test (prostaglandin Ej with ADF). Addition of the endogenous inhibitor PGE] renders the ADF HS assay more sensitive than the ADF assay.

Aggregation curves were recorded for 6 minutes and analyzed with Dynabyte Medical software. The following platelet adhesion parameters were calculated:

1) Amax, maximum value of platelet adhesion in units of relative adhesion (AU);

2) AUC, total area under the aggregation curve (AU * min). Their effect is the total height of the aggregation curve and its slope and 1-axis are best suited to express the total platelet activity.

Statistics. Results were expressed as mean and mean standard error (Mean ± SEM). A one-way ANOVA test was used to assess the reliability of the differences. If the null hypothesis was rejected, a post-hoc Student-Newman-Keuls test was used.

Results. The first series of tests were designed to investigate the effects of different concentrations of active substances in combination. As shown in Table 1. MD over a wide range of concentrations provides significant protection against ADF + PGE] -induced platelet adhesion. Amax was reduced from 100% in the control to 55-58% in the MD 10 ' ⁵ and IO ⁴ groups. NS (10 ^-4 mmol / ml) also reduced ADF-induced platelet aggregation. Combined action of both agents resulted in significantly higher and more pronounced reduction in platelet adhesion in the ADF or ADF + PGEi assay, which appears in both AUC and Amax data.

Table 1

Effects of MD, NS and combinations thereof on ADF and ADF + PGE] -induced platelet adhesion; Mean ± SEM; N-51

Group ADF ADF + PGE, AUC (AU * min) Amax AUC (AU * min) Amax AU % AU % Control 942 + 43.7 169.3 + 6.4 100 1005 + 46.5 175.3 + 8.9 100 MD 10 · ⁶ 897 + 23.4 159.5 + 4.4 94 874 + 31.0 151.8 + 5.2 87 MD 10 ' ⁵ 882 + 26.0 157.7 + 3.4 93 579 + 48.4 ** 96.6 + 48.3 ** 55 MD llri 869 + 36.3 153.2 + 6.1 90 587 + 37.4 ** 101.4 + 2.2 ** 58 NS KF ⁴ 859 + 62.5 148.0 + 5.2 * 87 862 + 51.9 146.7 + 8.6 84 MD Kri + NS 10 ' 4 474 + 34.9 ***** " 81 + 5.7 ***** " 48 306 + 35.5 **** " 54.5 + 5.8 ***** " 31st

* P <0.05 versus Control ** P <0.005 versus Control *** P <0.0005 versus Control **** P <0.00005 versus Control #P <0.005 versus Control 10 ^-4 P <0.0005 versus Control MD 10 ^{4 $} P <0.005 vs. NS 1 {F "PO, 0005 vs. NS 10 ^-4

Example 2. Effect of MD and NS on thrombosis

The method. We chose an experimental thrombosis model based on FeCF-induced rat arterial thrombosis (Kurz K et al, Thromb Res 1990; 60: 269-280. Wang X, Xu L, Thromb Res 2005; 115: 95-100). Oxidative damage of tissues with iron contributes to the adhesion of platelets to the damaged surface and adhesion, followed by activation of coagulation and precipitation of fibrin. Wistar male males weighing 350-420 g were used in the experiments. The rats were randomized into several study groups of at least 7 animals each. The solvent or test compound MD (25 mg / kg), NS (25 mg / kg) and combination MD + NS (25 + 25 mg / kg) were administered orally 2 hours prior to the initiation of thrombosis.

Rats were anesthetized with pentobarbital sodium (50 mg / kg, ip and 10 mg / kg / h) and placed on a heated operating table during the experiment to maintain a body temperature of 37 ° C. One of the carotid arteries was detected by a neck incision, separated from the surrounding tissue, the vagus nerve, and a flow probe (electromagnetic blood flow meter MFV 1200, Nicon Kohden, Japan) applied to the open total carotid artery. After 15 min. after a long period of stabilization, two pieces of Whatman filter paper (2x1 mm) soaked in 15% FeCl ₃ solution were induced by thrombosis upon application to the arteries in contact with the vascular tissue. The time of carotid thrombosis was recorded as the time at which the blood flow stopped completely and is shown as the time to occlusion (LLO).

The duration of the rat tail bleeding was further measured during the thrombosis experiment. The tail was cut with a scalpel 5 mm from the tip and immediately immersed in 37 ° C warm isotonic saline until the bleeding stopped. Bleeding stop was defined as the time to complete bleeding, when the bleeding did not recur within the next 30 s.

Statistics. The results were analyzed with Microsoft Excel 2007 software. Data are shown as mean ± VC from 7 to 8 individual animals / moons. Differences between experimental groups were compared using one-way ANOVA with repeated comparison (Tukeja test). P <0.05 was considered significant.

Results. The median time to FeCF-induced vascular thrombosis and the time to stop arterial flow induced by FeCF in the control group was 24.4 min. (Table 2).

Table 2

Effect of MD, NS, and a combination of both on FeCl ₃ -induced thrombosis; Mean ± SEM; N = 7-8

Group Time to Occlusion (LLO) Duration of tail bleeding min % min % Control 24.4 + 1.45 100 8.9 + 1.28 100 MD 25 mg / kg 29.8 + 2.29 122 10.5 + 1.01 118 NS 25 mg / kg 30.3 + 3.12 124 11.5 + 1.39 ' 129 MD + NS (25 + 25 mg / kg) 34.0 + 2.78 * 139 11.4 + 1.42 128

* P <0.05 vs. Control

MD at 25 mg / kg did not produce a significant increase in LLO. NS caused a small increase in LLO, which was not significant. The effect of NS on the duration of tail bleeding was also similar / not statistically significant. Unexpectedly, the combination of MD and NS resulted in a significant and significant increase in LLO (39%) without a significant increase in tail bleeding duration.

Given the effect of the combination of MD and NS on platelet adhesion in vitro and LLO prolongation in vivo, this combination may find use in reducing the risk of platelet adhesion and thrombosis in patients with severe atherosclerosis, possible myocardial infarction and stroke, and in the postoperative period. The fact that the combination of MD and NS does not prolong the duration of tail bleeding suggests the potential use of this combination in patients at increased risk of pre- and postoperative bleeding.

Example 3: Comparative study of MD / NS and LA / NS combined use to reduce NS induced redness

Nicotinic acid (niacin, NS) is effective in lowering serum cholesterol, LDL and triglycerides, while increasing HDL levels. However, in patients receiving the immediate or sustained release form of nicotinic acid, there is a limiting side effect: rapid, significant warming of the skin and vasodilation, which in many cases results in discontinuation of the drug (Gupta EK, Ito MK, Heart Dis 2002; 4: 124137). Laropiprant (MK-0524) (LA) has been proposed as one of the most active and promising means for reducing NS-induced redness (Cheng K et al, PNAS 2006; 103: 6682-6687). The aim of our study was to compare experimentally the effects of MD and LA on NS-induced redness (changes in skin temperature).

3.1. Assessment of skin temperature changes caused by nicotinic acid

Materials and methods. A contactless temperature measurement method was used to measure skin temperature changes in intact rats (Papaliodis D et al, Br J Pharmacol 2008; 153: 1382-1387). Temperature measurements were performed with a handheld infrared thermometer (Modei ProScan 510, TFA-Dostman). Animals were habituated to hand-picking and infrared probe 3 days prior to use. Three temperature measurements from the dorsal side of each ear were performed on non-narcotic animals immediately prior to NS (dorsal) or solvent a / test substance (tail) s.c. administration.

The ear temperature was then measured every 5 minutes for up to 60 minutes. over a long period. Between measurements, animals were returned to cages. For each time point, an average of six temperature measurements (three for each ear) was recorded. LA (MK 0524, Cayman Chemicals) was first dissolved in DMSO and then diluted with 0.9% NaCl daily before the experiment. The dose ratio of NS to LA in combination is based on the Tredaptive ™ (nicotinic acid / laropiprant) 1000 mg / 20 mg prolonged-release tablets.

Design of the experiment

Testing the effects of time and solvent on skin temperature

GROUP PROCEDURE Number of animals

SolvLA LA solvent 6

Solvent NS solvent 6

NS NS 15 mg / kg s.c. 6th

II Effects of NS / LA and NS / MD combinations on skin temperature

LA was administered concurrently with NS as NS + LA [0] or 30 min, previously as NS + LA [30], MD was administered concurrently with NS as NS + MD [0] or 30 min. previously as NS + MD [30]; the effects of LA and MD on skin temperature were also tested.

GROUP Control / Solvent PROCEDURE Number of animals NS NS 15 mg / kg 6th LA LA 0.3 mg / kg 6th NS + LA NS 15 mg / kg + LA 0.3 mg / kg 6 * MD MD 45 mg / kg 6th NS + MD NS 15 mg / kg + MD 45 mg / kg 6 * * in each time group

Statistics. Data were analyzed with Microsoft Excel software and results expressed as Mean +/- Mean Standard Error (Mean + SEM). The mean scores of the different groups were compared using one-way ANOVA and t-Student test. P <0.05 was considered significant.

Results. The mean ear temperature was 28.1-30.2 ° C, recorded between 10am and 2pm. A study of the response to NS over time (15 mg / kg sc) showed a maximum temperature increase of 2.32 + 0.37 ° C against the initial temperature and 2.57 + 0.43 ° C against the solvent group (P <0.005). after 10 minutes (Image). The effect of LA solvent on ear temperature was found to be significantly different from that of NS and MD only in the first 5 minutes after injection, so only one control group was used.

Picture. Effect of NS, NS solvent and LA solvent on rat ear skin temperature * P <0.05 vj

Subcutaneous injection of MD or LA did not cause significant changes in rat ear skin temperature (Table 3). Simultaneous administration of NS and MD (NS + MD [0] group; pre-emptive time = 0) resulted in a decrease in NA redness similar to that co-administered with NS and LA. The NS-induced increase in temperature was reduced to 67 and 69%, respectively (Table 3). No temperature difference was observed between MD + NS [0] when MD was co-administered with NS and MD + NS [30] when 45 mg / kg MD was administered for 30 min. ahead of NS. In our experiment, only the prior administration of LA s.c. at a dose of 0.3 mg / kg for 30 min. caused significant protection against NS-induced skin temperature increase before NS injection (Table 3).

Table 3

Effect of LA and MD on NS-induced changes in skin temperature, N = 6, Mean + SEM

Group Initial temperature, “C Maximum temperature, ° C An increase, % Control / Solvent eater 29.5 + 0.29 29.62 + 0.25 " - NS 29.61 + 0.4 32.2 + 0.42 *** 100 LA 29.43 + 0.27 29.5 + 0.35 " - NS + LA fol 29.72 + 0.31 31.45 + 0.40 ** 67 NS + LA F301 29.51 + 0.32 30.73 + 0.34 * ⁵ 47 MD 29.42 + 0.38 29.7 + 0.31 " - NS + MD Γ01 29.53 + 0.29 31.33 + 0.48 * 69 NS + MD f301 29.68 + 0.26 31.40 + 0.39 * 65

* P <0.05 versus Control ** P <0.005 versus Control *** P <0.0005 versus Control ^J P <0.05 versus ^{Control iJ $} P <0.0005 versus Control

3.2. Skin vasodilation study

Materials and methods. Wistar male rats are anesthetized with pentobarbital sodium (50 mg / kg i.p.) and anesthetized with additional doses (10 mg / kg) every hour. Blood pressure is measured in the left carotid artery, recorded on a standard ECG lead II. Blood flow in the right ear artery was measured with a laser Doppler flow meter (OXYFLOW 2000, USA). Blood flow, ECG, and arterial pressure were recorded with AD Instruments PowerLab systems and stored on a computer for further processing. After 10 min. long baseline enrollment of test substances was injected s.c. at the withers and continued registration for another 30 min. Mean blood flow data for each animal were calculated from mean blood pressure and compared with baseline and control. Results were calculated from 5 to 7 separate experiments and expressed as% change in maximal blood flow to baseline (Carballo-Jane E et al, J Pharmacol Toxicol Methods 2007; 56 (3): 308-316). Test substance solutions were prepared as described in section

3.1.

EXPERIMENT PLANNING

GROUP NS and MD solvent PROCEDURE Number of animals NS NS 15 mg / kg 7th LA solvent 5 LA LA 0.3 mg / kg 6th LA + NS [0] LA 0.3 mg / kg + NS 15 mg / kg 6th LA + NS [30] LA 0.3 mg / kg + NS 15 mg / kg 7th MD MD 45 mg / kg 6th NS + MD [0] NS 15 mg / kg + MD 45 mg / kg 6th NS + MD [30] NS 15 mg / kg + MD 45 mg / kg 6th

LV 1446i

Statistics. Results were expressed as mean ± mean standard error (Mean ± SEM). Within the group, statistical analysis was performed by Student's t-test. Differences between experimental groups were compared using one-way ANOVA with repeated comparison (Tukey's test). P <0.05 was considered significant.

Results. Administration of MD, as in the case of LA, caused only insignificant changes in blood flow. When NS was co-administered with MD (bypass time = 0), the increase in blood flow was slower and less pronounced than with co-administration of NS and LA (LA + NS [0], see Table 4). There was no significant difference in blood flow between MD + NS [0] when MD was co-administered with NS and MD + NS [30] when 45 mg / kg MD was administered for 30 min. ahead of NS. In our experiment, only pre-LA administration for 30 min. pre-NS (NS + LA [30]) significantly reduced NS-induced increase in blood flow to rat ear vessels (Table 4).

Table 4

Effect of MD and LA on ND-induced vasodilatation of the skin; N = 5-7, Mean ± SEM

Group Changes in blood flow, % NS and MD solvent 2.12 ± 1.66 ^si NS 52.27 + 8.5 ** MD 6.04 + 2.02 ⁵ NS + MD [0] 25.11 + 5.25 * ^s NS + MD [30] 28.07 + 5.74 * ' LA solvent 7.31 + 1.93 ⁵⁵ LA 9.87 + 2.60 ⁵ NS + LA [0] 29.34 + 7.82 * NS + LA [30] 16.32 + 6.21 ⁵

* P <0.05 versus solvent ** P <0.005 versus solvent ^s P <0.05 versus NS ^IS P <0.005 versus NS

Summary. The ability of MDs to antagonize NS-induced peripheral vasodilation may have a beneficial effect in the clinic in reducing the effect of nicotinic acid on the skin (redness). In our experiments, we did not find any advantage in the simultaneous administration of NS and LA compared to the simultaneous administration of NS and MD.

Thus, we unexpectedly found that the combination of NS with MD has a synergistic effect on the prevention of platelet adhesion and a reduced side effect of redness.

Methods of implementing the invention

The term "combination medicinal product" as used herein, means the simultaneous, sequential or separate administration of components of a combination. The invention thus described provides for the simultaneous, sequential or separate administration of a combined medical product comprising NS and MD or pharmaceutically acceptable salts thereof for the prevention of platelet adhesion disorders. The combination medical product of the invention may be administered in the form of a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition comprising NS or a pharmaceutically acceptable salt thereof, and MD or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

The pharmaceutical composition of the present invention also comprises separate pharmaceutical compositions, wherein the first composition comprises NS or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, and the second composition comprises MD or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. Such a composition requires sequential or separate use. Since the prevention or treatment of metabolic-related disorders involves the prolonged use of a medical product, the best way of realizing the invention is through a form suitable for oral use, such as tablets or capsules. The amount of each active ingredient in the pharmaceutical composition of the combination described may vary depending on the condition being treated. Metabolic disorders specialists can easily select the appropriate amount of each active ingredient and the appropriate dosage regimen. The preferred ratio of active ingredient NS to MD or salts thereof is 3: 1 to 1: 3.

According to a further aspect of the invention there is provided the use of a combination medical product or pharmaceutical composition as defined herein for the manufacture of a medicament for simultaneous, sequential or separate use in the treatment or prevention of platelet adhesion disorders.

Claims (7)

A therapeutic combination of nicotinic acid for the prevention and / or treatment of a disorder associated with platelet adhesion, comprising an effective amount of nicotinic acid or a pharmaceutically acceptable salt thereof, and an effective amount of meldonium or a pharmaceutically acceptable salt thereof. The combination according to claim 1, wherein the nicotinic acid or a pharmaceutically acceptable salt thereof is in the form of a fast-acting, slow-acting or sustained-acting pharmaceutical formulation. The combination according to claim 1, wherein the meldonium or pharmaceutically acceptable salt thereof is in the form of a fast-acting, slow-acting or sustained-acting pharmaceutical formulation. A pharmaceutical composition for the prophylaxis and / or treatment of a disorder associated with platelet adhesion, particularly thrombosis and thromboembolism, comprising an effective amount of nicotinic acid or a pharmaceutically acceptable salt thereof, and an effective amount of meldonium or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. carrier. The composition according to claim 4, wherein the nicotinic acid or a pharmaceutically acceptable salt thereof is in the form of a fast-acting, slow-acting or sustained-acting pharmaceutical formulation. The composition according to claim 4, wherein Meldonium or a pharmaceutically acceptable salt thereof is in the form of a fast-acting, slow-acting or sustained-acting pharmaceutical formulation. The composition according to claim 4, comprising about 50-500 mg nicotinic acid or a pharmaceutically acceptable salt thereof and about 50-500 mg meldonium or a pharmaceutically acceptable salt thereof.