Using beta-blocking agent-containing pharmaceutical preparation

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to using a pharmaceutical preparation comprising beta-blocking agent in the maintenance dose less 50 mg, in particular, in the range from 25 mg to 47 mg in mixture with a pharmaceutically acceptable adjuvant, vehicle or carrier. The preparation is used in treatment of atherosclerosis and diseases associated with thereof. Invention provides decreasing dose of the preparation.

EFFECT: improved using method.

6 cl, 3 tbl, 1 ex

 

The scope of the invention

The present invention relates to pharmaceutical preparations containing beta-blocker at a maintenance dose of less than 50 mg in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and the method of treatment and the use of drugs for the treatment of atherosclerosis and related conditions.

Prior art

There is a continuing need for new drugs to further reduce the risk of atherosclerotic disease, as it is one of the most common diseases in industrialized countries.

As is known, various pharmaceuticals, such as the group known as beta-blockers, have positive effects on various cardiovascular diseases, although the impact on the atherosclerotic disease little is known. It was shown that beta-blockers reduce the cases of myocardial infarction and mortality in the secondary (The Norwegian Multicenter Study group, N Engl J Med 304:801-807, 1981; Olsson et al., J Am Coll Cardiol, 5:1428-1437, 1985; MERIT-HF Study Group, Lancet, 353:2001-2007, 1999) and primary care research (Wikstrand et al., JAMA, 259:1976-1982, 1988). In animal studies, beta-blockers reduce the degree of atherosclerosis caused by diet (Östlund-Lindqvist et al., Arteriosclerosis, 8:40-45, 1988) and stress (Kaplan et al., Eur Heart J, 8:928-944;Pettersson et al., Curr Op in Cardiol 3:S9-S14,1988), but still no presents no direct evidence in humans antiatherosclerotic effect of beta-blockers, similar to the effects of statins on intima-medial thickness (IMT) of the carotid artery.

Introduction the combination of selective β1-blockers and drugs that lower lipid levels, healthy volunteers in order to observe the effects exerted on the metabolism of fats, ammonia level and perception of workload during exercise, described in Br. J Clin Pharmacol 1997, vol 43, no 3, pages 291-300. The investigated combinations were: (1) metoprolol (controlled release) and fluvastatin, (2) metoprolol (controlled release) and bezafibrat, (3) atenolol (regular release) and fluvastatin and (4) atenolol (regular release) and bezafibrat. The article concluded that each of these four combinations caused a significant decrease in fat metabolism, increased the concentration of ammonia in plasma and increased perception of physical exercises. The combination of (1) have the least side effect, but believed that the difference in products is a significant factor to explain the differences observed in relation to the combination (3).

About the effectiveness of the combination of pravastatin and atenolol in patients with hypertension and hypercholesterolemia together and in Scand. J. Print Health Care 1999, vol 17, 122-127. It was concluded that the efficiency of atenolol was not affected by co-administration of pravastatin and Vice versa. However, the impact of lifestyle was also a feature of this study, and therefore the conclusions that can be drawn from this study are not completely accurate.

On post hoc analysis of patients who had been treated with lovastatin and which also received anti-hypertensive medication, including blockers β1-adrenergic receptors reported in Hypertension, 1992, Vol.19, 3, 242. The article concludes with the limitations that the attenuation caused by lovastatin changes in lipids and lipoproteins or modify protective nature of lovastatin in the introduction together with commonly used anti-hypertensive agents is not confirmed.

In Presse Med Volume 1996, vol 25, no.40, 2013-2016, it was concluded that the effectiveness of atenolol blocker β1-adrenergic receptors was reduced in combination with pravastatin. However, the effectiveness of pravastatin on lipid metabolism was more favorable when pravastatin combined with captopril, an angiotensin-converting enzyme, but not by atenolol.

Reported low doses of metoprolol to treat hypertension and heart disease, but these messages indicate that the use of lower doses of metoprolol has PE the temporal degrees of effectiveness. Westergren et al. in Current Therapeutic Research, 1994 vol.55, No. 2, 142 describe the application of doses of metoprolol 50 mg (half of the most commonly used daily dose of metoprolol immediate release) in the form of a controlled-release tablets for the treatment of hypertension in degree from mild to moderate. They report that this dose of metoprolol is well tolerated. However, Sanderson et al. according to the British Heart Journal, 1995, vol.74, 502, that a low dose of metoprolol 6.25 mg, administered twice a day can be dangerous for patients with severe heart failure.

Garnett in a review in the American Journal of Health-System Pharmacology, 1995, vol.52, 1639 describes the pharmacokinetic profiles of inhibitors of HMG-CoA-reductase and analyzes specific drug interactions that have been well documented.

In WO 98/02357 described packaging for delivery of pharmaceutically active substances or combinations thereof. One of these mentioned combinations is a combination of a beta-blocker such as metoprolol or isosorbide Mononitrate, and substances, lowering lipid levels, such as fluvastatin. In this application not described any data on the effectiveness of this combination.

In WO 99/11260 described, the combination of atorvastatin and hypotensive agent. No data in this application are not described.

In WO 97/38694 described the combination of an inhibitor of HMG-CoA-reductase (3-hydroxy-3-methylglutaryl is-coenzyme-A-reductase) with folic acid in combination with drug selected from a number of medicines other types, including beta-blockers.

In WO 00/38725 described the combination of an inhibitor of the transport of bile in the ileum and some medicines other types, including anti-hypertensive drugs, such as beta-blockers, no data is presented.

Summary of the invention

The present invention relates to pharmaceutical preparations containing beta-blocker at a maintenance dose of less than 50 mg, in particular in the range from 10 to 47 mg, especially in the range 25-47 mg, in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, and to a method of treatment and the use of such agents for the treatment of arteriosclerosis, including atherosclerosis, caused by diet and stress, coronary atherosclerosis, carotid plaques, hypertension, diabetes, stroke, necrosis of the vessels of the heart, angina, alternating lameness and myocardial infarction.

Detailed description of the invention

Unexpectedly, it was found that low dose beta-blocker, especially metoprolol may reduce the rate of increase in BMI carotid artery in clinically healthy subjects not detect symptoms of the disease, carotid plaques, which also indicates a favorable effect in the development of atherosclerosis.

In one aspect of us is Aasee the invention relates to pharmaceutical drug, contains beta-blocker in a maintenance dose in the range 25-47 mg in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The dose of beta-blocker is preferably less than 30 mg, and most preferably 25 mg

In this application, the term "beta-blocker" refers to any pharmaceutical agent, which in the framework of its pharmacological action blocks beta-1 receptors. In addition, in this application, the term "beta-blocker" includes chemical modification of beta-blockers, such as esters, stereoisomers, prodrugs and metabolites, either active or inactive, and any pharmaceutically acceptable salt or solvate, or a solvate of such a salt.

The phrase "maintenance dose less than 50 mg" in this application refers to the highest dose of any beta-blocker that blocks beta-1 receptors to the same extent as 47 mg of metoprolol succinate.

The degree of blockade of beta-1-receptor is defined as the reduction in the increase of heart rhythm caused by exercise, within 24 hours.

Beta-blockers are indicated in this application include compounds selected from the group consisting of acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, boukouvala, buretrol, BU is uralla, bunitrolol, bupranolol, butoverall, carazolol, carteolol, carvedilola, celiprolol, atemolol, coronella, dilevalol, epanolol, indenolol, labetalola, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, natokalau, nebivolol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, spinella, calendula, tertatolol, tilisolol, timolol, celiprolol and xianyou and their stereoisomers, their pharmaceutically acceptable salt or solvate, or solvate of such a salt, but not limited to.

In the present invention is a beta-blocker, respectively, represents metoprolol or atenolol, and their stereoisomers, their pharmaceutically acceptable salt or solvate, or a solvate of such a salt. In particular, a beta-blocker is a succinate metoprolol (described in U.S. patent 5001161), metoprolol tartrate or metoprolol fumarate.

Therefore, in another embodiment of this aspect of the invention, the beta-blocker is a metoprolol or its pharmaceutically acceptable salt, or MES such salts. Metoprolol may be in the form of metoprolol succinate, tartrate metoprolol or fumarata of metoprolol.

For clinical use of beta-blocker is prepared in the form of a pharmaceutical preparation for oral, nutrive the tion, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, transbukkalno, rectal, parenteral or some other way of introduction. The pharmaceutical preparation contains a beta-blocker in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The total number of active component is in the range from about 0.1% (wt./wt.) to about 95% (wt./wt.) of the drug, respectively, from 0.5% to 50% (wt./wt.) and, in particular, from 1% to 25% (wt./wt.).

In another aspect, the present invention relates to a pharmaceutical preparation containing a beta-blocker during the maintenance dose less than 50 mg and agent that lowers cholesterol, such as an inhibitor of HMG-CoA-reductase. Inhibitor of HMG-CoA reductase inhibitor can be a statin is selected from atorvastatin, tseriwastatina, fluvastatin, itavastatin, lovastatin, mevastatin, mycostatin, mevastatin, pravastatin and simvastatin or its pharmaceutically acceptable salts, especially sodium or calcium, or MES or MES such salts. An example of such a statin is a compound with the chemical name (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)-amino]-pyrimidine-5-yl](3R,5S) - for 3,5-dihydroxide-6-ANOVA acid and its calcium and sodium salts (about isany in the application for the European patent EP-A-0521471 and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444). Preferred beta-blockers and the preferred dose of these beta-blockers are as defined above.

In this application, the term "agent that lowers cholesterol" includes chemical modification of inhibitors of HMG-CoA-reductase, such as esters, stereoisomers, prodrugs and metabolites, either active or inactive. Agent, lowering cholesterol, any dose used in clinical practice, can be used in the preparations according to the present invention.

The molar ratio of beta-blocker and agent, lowering cholesterol, can be in the range from about 1000:1 to about 1:1000. The molar ratio of beta-blocker and agent, lowering cholesterol, lies respectively in the range from 300:1 to 1:300, in particular from 50:1 to 1:50.

When the pharmaceutical preparation of the present invention the active ingredients can be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable component, as well as with disintegrating agents and oiling agents, such as magnesium stearate, calcium stearate, sodium fumarate and waxes of polyethylene glycol. The mixture can then be processed in the city is annuli or compressed into tablets.

Active components separately can be pre-mixed with other inactive components before mixing to prepare the drug. Active components can also be mixed with each other before mixing with inactive components for the preparation of the drug.

Soft gelatin capsules can be prepared with capsules containing the active ingredient according to the invention, vegetable oil, fat, or other suitable media for soft gelatin capsules. Hard gelatin capsules may contain granules of the active component. Hard gelatin capsules may contain the active ingredient in combination with solid powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Unit dose for rectal injection can be prepared (1) in the form of suppositories which contain the active substance is mixed with a neutral fat base; (2) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable media for gelatin rectal capsules; (3) in the form of ready-to-use micro; or (4) in the form of a drug with a dry micro to be diluted in under adamem solvent just before the introduction.

Liquid preparations can be obtained in the form of syrups or suspensions, for example solutions or suspensions containing the active components and residue containing, for example, sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If required, such liquid preparations may contain colouring agents, flavouring agents, preservatives, saccharin and carboxymethyl cellulose or other thickeners. Liquid preparations can also be prepared in the form of a dry powder that is diluted in a suitable solvent before use.

Solutions for parenteral administration can be prepared in the form of a solution of the preparation according to the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing components, preservatives and/or buffer components. Solutions for parenteral administration can also be obtained in the form of a dry product that is diluted in a suitable solvent before use.

The dose of a compound, you need to put in will depend on the relevant evidence, age, weight and sex of the patient and can be determined by a doctor. Dosage, in particular, will be in the range from 0.01 mg/kg to 10 mg/kg, but the overall daily dose will not exceed 50 mg

Medical and pharmaceutical application

Also according to the present izaberete the Oia provides a use of a pharmaceutical product contains beta-blocker at a maintenance dose of less than 50 mg, in particular less than 30 mg, and is preferably in the range 25-47 mg and, in particular, at a dose of 25 mg in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, in drug therapy and, in particular, for use in prophylactic and therapeutic treatment of atherosclerosis; the use of such drug in the manufacture of medicaments for use in the prophylactic or therapeutic treatment of atherosclerosis and methods of treatment or prevention, which is administered a therapeutically effective amount of a beta-blocker during the maintenance dose, described immediately above, the patient suffering from atherosclerosis or susceptible to it.

Assume that the term "drug therapy", as used here, includes preventive, diagnostic and therapeutic regimes, carried out in vivo or ex vivo in humans or other mammals.

Expect the preparations according to the invention will be useful for prophylactic and therapeutic treatment of atherosclerosis, in particular for patients suffering from coronary atherosclerosis or carotid plaques, or susceptible to them.

In addition, expect that the preparations according to the invention will be useful for prophylactic and therapeutic treatment of cardio-the vascular complications in General, which include arteriosclerosis, including atherosclerosis, caused by diet and stress-induced necrosis of the vessels of the heart, hypertension, diabetes, angina, alternating lameness, myocardial infarction, including acute myocardial infarction, and stroke, but not limited to.

Expect the preparations according to the invention will be particularly useful for the prevention of clinical cases associated with progression of atherosclerosis, and/or acute vascular damage associated with atherosclerotic disease and plaques. These injuries include stroke, myocardial infarction (MI), the weakening of mental abilities, peripheral vascular disease and renal dysfunction, but are not limited to.

In another aspect, the present invention relates to a pharmaceutical preparation containing a beta-blocker in a maintenance dose in the range 25-47 mg in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the manufacture of medicaments for use in the treatment or prevention of congestive heart failure (SN) or necrosis of the vessels of the heart in susceptible patients. The dose of beta-blocker is preferably less than 30 mg, and most preferably 25 mg Possible drug contains an agent that lowers cholesterol, as described above.

In olnamespace the present invention relates to sets of components, including:

1) a vessel containing a beta-blocker during the maintenance dose less than 50 mg, preferably in the range 25-47 mg, and

2) a vessel containing an inhibitor of HMG-CoA-reductase, which is an (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl](3R,5S) - for 3,5-dihydroxide-6-envoy acid or its pharmaceutically acceptable salt, especially sodium or calcium, or MES or MES of such salt,

and instructions for sequential, separate or simultaneous introduction of a beta-blocker and an inhibitor of HMG-CoA reductase inhibitor to a patient for which this introduction is necessary or useful.

Another aspect of the invention relates to sets of components, including:

1) a pharmaceutical preparation containing a beta-blocker during the maintenance dose less than 50 mg, preferably in the range 25-47 mg, in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

2) pharmaceutical preparation containing an agent that lowers the level of cholesterol in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier;

where a beta-blocker and an agent that lowers cholesterol, each presented in a form that is suitable for administration in conjunction with the other.

The term "introduction together with the authors imply that the appropriate preparations containing bet the a-blocker and agent, lowering cholesterol levels is administered simultaneously, sequentially or separately during the course of treatment of the relevant condition, which may be acute or chronic. In particular, the term means that the two drug injected (possibly again) close enough in time to have a beneficial effect on the patient, which is more significant during the course of treatment of the relevant condition, than the introduction of (possibly repeated) any of the two drugs separately, in the absence of another drug within the same treatment. It is necessary, however, to emphasize that beta blockers have never been used to obtain anti-atherosclerotic effect, for example in patients suffering from hypercholesterolemia or hyperlipoproteinemias. The decision, whether the connection is more significant favorable effect in relation to the particular condition and during the course of treatment for this condition will depend on the condition which must be treated or prevented, but can be easily achieved by a person skilled in the technical field.

Thus, the term "in conjunction with" means that one or the other of the two drugs can be entered (possibly again) before, after or at the same time as another component. When used in this context, the terms "introduced at the same time, what about the" or "was introduced at the same time" means, that individual dose of beta-blocker and agent, lowering cholesterol, was administered within 48 hours, for example 24 hours, one after the other.

The following example serves to illustrate, but not limit the scope of the invention.

Example

Large-scale clinical trial was designed to study the effect of beta-blocker metoprolol low dose on the progression of IMT of the carotid artery compared with placebo, and results of clinical measurements during double-blind treatment period of 36 months from the subjects, not detecting symptoms of the disease, carotid plaques. The study was a randomized, double-blind, parallel, placebo-controlled, single center study.

Included in the study population consisted of men and women, not detecting symptoms of the disease, aged 49 to 70 years, with plaques in the right carotid artery. 50% random sample of those who took part in the study, were selected to participate in the study on the epidemiology of carotid artery disease. 1548 subjects underwent investigation for inclusion in the list (one visit), including medical history, medical examination, laboratory measurements and two-dimensional ultrasound examination of the right carotid artery in b-mode. Subjects with established damage is in the right carotid artery and those who had no contraindications to the study Protocol were invited to participate. Just 793 subject were eligible for randomization. All participants gave written consent, based on the received information. The main criteria for exclusion served as myocardial infarction, angina or stroke in history within the previous three months, surgical intervention in the right carotid artery in the history of the disease, regular use of beta-blockers or statins, systolic blood pressure above 160 mm Hg or diastolic blood pressure above 95 mm Hg, hypercholesterolemia (>8.0 mmol/l), hyperglycemia, if you want or there is a suspicion on the need for insulin treatment, and conditions that, in the opinion of the investigator, made the subject unsuitable for testing.

The randomization procedure was produced by using computer-generated randomization scheme. Participants randomly distributed according to the plan factorial experiment in one of four groups according to the combination of drug: placebo/placebo, metoprolol (25 mg .d.(once a day)/placebo fluvastatin (40 mg .d.)/placebo or metoprolol (25 mg .d.)/fluvastatin (40 mg o.d.). Placebo produced exactly like the tablets of metoprolol CR/XL (AstraZeneca AB, Möextremely flammable (DME propellant, Sweden) and capsules fluvastatin (Novartis Ltd, Basel, Switzerland) line is the result.

The primary outcome measure was a change in the average value of intima-medial thickness (mean BMI) of the common carotid artery (segment length of 10 mm) and changes in the maximum value of intima-medial thickness (maximum BMI) of the bulb of the carotid artery. The nature of safety and tolerability during treatment with fluvastatin and metoprolol was evaluated by comparing the adverse events and laboratory data of the study with placebo. Controlled death and the frequency of major cardiovascular cases.

Each participant was examined four times during the first year (after one, three, six and twelve months) and every 6 months thereafter. Weight was measured every six months, and lipid profile in a state of starvation (total cholesterol, LDL-lipoprotein, HDL-lipoprotein, and triglycerides) were determined each year. The liver transaminases (aspartate-aminotransferase (AST), alanine-aminotransferase (ALT)and creatine kinase (ck) was determined at each visit during the first year and then every year after that. Believed that the upper limit for the values of AST or ALT≥3 times and values of IC≥10 times increased during the study. Ultrasound examination of the carotid artery was performed at the baseline values and after 18 and 36 months of treatment. Subjects with high content of cholesterol is Rina or triglyceride recommended a diet low in fat, and if there was data on constant high values of cholesterol, such entities were sent to an independent specialist lipid disorders, uninformed about the participation of subjects randomised. With other conditions, such as high blood pressure, congestive heart failure, or abnormal laboratory values during the testing was done in accordance with existing regulations. At each visit, each participant was asked about any hospitalization, acute myocardial infarction and stroke, which occurred since the last visit. Vital status was determined for all subjects at study end.

During all tests were performed using a computerized tomography system Acuson 128 (Acuson 128 Computed Tomography System(Acuson, Mountain View, California) with sensor 7 MHz. The procedure of examination and image analysis, as described in another source (Wendelhag et al., Clin Physiol, 11:565-577, 1991; Wendelhag et al., Stroke, 28:2195-2200, 1997), conducted with the help of specially trained professionals sonographer certified on the implementation of a comprehensive curriculum (Berglund et al., J Intern Med, 236:581-586, 1994). Briefly, the bifurcation of the right carotid artery was scanned within a predetermined period, comprising three centimeters of the distal common carotid artery, bifurcation and one centimeter of the internal and external carotid arteries, respectively the military for the presence of plaques, defined as the focal intima-medial thickening more than 1.2 mm, the Thickness of intima-medial complex was measured at the far wall in accordance with the most advanced principle that uses a specially designed automated analyzing system images based on the automatic registration of the structures reflecting the signals, but with the option of making adjustments by the operator. Each image was analyzed, not having information about the group randomization of subjects.

From previous experience (Furberg et al., Circulation, 90:1679-1687, 1994) it was expected that the annual average rate of progression of IMT of the carotid artery in the group receiving placebo, will be approximately 15 microns per year with a standard deviation of 30 μm. The sample size of 200 subjects per group, i.e. a total of 800 people, was determined on the basis of the degree of abstinence 20%, the significance level of 5% (two-sided), a power of 0.90 and treatment ≥75% (fluvastatin) and 30% (metoprolol), respectively. The main dependent variables, the change in the average BMI of the common carotid artery (CCA) and the maximum BMI bulbs were analyzed in the linear model with change in BMI as the dependent variable and treatment as factors. Baseline values of BMI and the time between measurements were included in the model as covariants.

R is homesale led to a balanced treatment groups (see Table 1). The average baseline LDL cholesterol was 4.1 mmol/L. this treatment at basic values, or during tests for other cardiovascular compounds (e.g., diuretics, calcium channel blockers, ACE inhibitors (angiotensin converting enzyme), aspirin and postmenopausal hormone replacement therapy for women) was similar in the treatment groups (data not shown). The average observation period was up 35.9 (range from 8 to 40) months.

Metabolic and physiological effects treatment

Metoprolol increased serum triglycerides by 0.14 mmol/l compared with the group receiving placebo, but no effect on other metabolic variables were not observed. Compared with the group receiving placebo, the average heart rate decreased in the group receiving metoprolol, 2.5 stroke per minute, while blood pressure and lumen diameter did not change significantly.

Therapeutic effect on BMI carotid artery

Basic data of ultrasound studies are given in Table 1 and 2. The observed annual average rate of progression of IMT of the common carotid artery in the group receiving placebo was 13±53 μm. The annual rate of progression of maximum BMI in the bifurcation in the group receiving placebo was 89±154 μm. Fluvastatin,but not metoprolol, reduced the rate of progression of the average BMI of the common carotid artery compared with the group receiving placebo, after 36 months of treatment (mean difference in annual change between groups: - 9,95%confidence interval [Cl]: -15 to -3 μm, p=0.002), table 2-3.

Metoprolol was effective at slowing the rate of progression of maximum BMI of the bulb of the carotid artery compared with placebo after 36 months of treatment (mean difference in annual change between groups: -23,95%, Cl: -44 to -3 μm, p=0.014), table 2-3. This effect was already evident after 18 months of treatment (mean difference in annual change between groups: -58,95% Cl: from -94 to -23 μm, p=0.004). Metoprolol CR/XL also reduced the rate of progression of maximum BMI bulbs after 36 months of treatment in the subgroup with the level of serum cholesterol ≥6.5 mmol/l at baseline values (mean difference in annual change between groups: -53,95%, Cl: from -87 to -19 μm, p=0.001).

The frequency of cardiovascular events during the observation

The eighteen participants were cardiovascular (CVD) case (one subject suffered a fatal and seven non-fatal myocardial infarction, two died suddenly from coronary heart disease, and eight suffered a non-fatal blow). Frequency CVD cases tended to decrease in the group receiving metoprolol, compared to what Ruppel, receiving placebo (5 cases vs. 13, p=0,055). The corresponding figures in the groups receiving fluvastatin and placebo was 7 and 11 cases, respectively, p=0,350.

Portability

Continuous abstinence from randomized treatment was 15% in the group receiving metoprolol, 21% in the group receiving fluvastatin, and 23% in the group receiving placebo. The frequency of symptoms in the group with combination of two drugs was 25%. Women in the group receiving fluvastatin, compared with the group receiving placebo, there was an increased frequency temporarily high levels of liver enzymes (10,2% against 1.8%). The rate of serious adverse events and cancer did not differ between the treatment groups.

TABLE 1
FeaturesMedical group
Placebo / placeboMetoprolol / placeboMetoprolol / fluvastatin
Floor
Men, n (%)92 (46,2)89 (44,7)86 (43,7)
Women, n (%)107 (53,8)110 (55,3)111 (56,3)
Age(years)61,9±5,461,1±5,6 62,2±5,2
Smokers (%)57 (28,6)63 (31,7)66 (33,5)
The body mass index (kg/m2)25,6±3,725,6±3,825,4±3,4
Systolic blood pressure (mm Hg)139,1±14,6137,9±15,0139,1±13,7
Diastolic blood pressure (mm Hg)84,5±8,084,5±6,984,8±6,6
Heart rate (beats/min)69,5±9,068,9±8,470,2±9,0
Hypertension in medical history, n (%)22 (11,1)21 (10,6)24 (12,2)
The serum cholesterol (mmol/l)6,05±0,986,14±1,036,14±0,93
≥6.5 mmol/l, n (%)66 (33,2)70 (35,4)68 (34,7)
LDL (mmol/l)4,1±0,94,2±1,04,2±0,9
HDL (mmol/l)1,40±0,411,35±0,371,39±0,35
Triglycerides (mmol/l)1,21 (0,48-3,57)1,18 (0,46-4,57)1,12 (0,41-br4.61)
Hyperlipidemia in medical history, n (%) 31 (15,6)42 (21,1)37 (18,8)
Blood glucose when fasting (mmol/l)5,1±0,95,2±0,75,1±0,6
NIDDM in medical history, n (%)10 (5,0)7 (3,5)5 (2,5)
CVD in medical history, n (%)7 (3,5)8 (4,0)8 (4,1)
Ultrasonography of the carotid artery
The average BMI of the common carotid artery (µm)898±171920±197903±205
Maximum BMI bifurcation bulbs
carotid artery (µm)1875±5051936±6511970±652

Selected baseline characteristics of participants randomized BCAPS (lowering the cholesterol level under the action of beta-blockers in subjects not detect the symptoms of the disease with plaques; Beta-blocker cholesterol-lowering asymptomatic plaque study) study in accordance with the treatment group.

Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein; NIDDM, non-insulin-dependent diabetes mellitus; CVD, cardiovascular disease; BMI, intima-medial thickness of the ina.

TABLE 2
FeaturesMedical group
PlaceboMetoprololPlaceboFluvastatin
The average BMI of the common carotid
artery (µm)
The number of subjects390393394389
Basic (±SD)893±170912±202910±186895±188
18 months (±SD)896±176908±205913±186890±196
36 months (±SD)917±203934±220945±216905±205
Δ18 months basic (±SD)3±10-5±123±11-5±11
Δ36 months basic (±SD)24±1322±1336±1511±11
Δ between groups at
36 months (95% Cl)-2 (-20 to 17)-25 (-44 to -7)
The average BMI of bifurcation
carotid artery (µm)
The number of subjects369364375358
Basic (±SD)1875±5411936±6341886±5701926±609
18 months (±SD)1982±5721937±5721954±5891965±554
36 months (±SD)2133±6302003±6242097±6702095±652
Δ18 months basic (±SD)112±37623±32572±37363±334
Δ36 months basic (±SD)227±421154±411211±455170±374
Δ between groups at
36 months (95% Cl)-73 (from depression -133 to -13)-41 (from -102 to 19)

Mean values and mean change intima-medial thickness of the common carotid artery and the bifurcation of the carotid artery in basic research and at 18 and 36 months of the study in accordance with the treatment groups. BMI, intima-medial thickness; SD, standard deviation; Cl, confidence interval.

TABLE 3
The measurement resultThe treatmentβfactorStandard errorA value of p
The average BMI SSAFluvastatin
18 months-0,01350,0080,077
36 months-0,02750,0090,002
Metoprolol
18 months0,00490,0080,524
36 months0,00120,0090,897
Maximum BMIFluvastatin
bifurcations18 months0,00090,0290,940
36 months-0,01320,0130,329
Metoprolol
18 months-0,03670,0130,004
36 months-0,03330,0130,014

Therapeutic effects for 36 months on the progression (in microns) mean BMI common carotid artery and maximum BMI of bifurcation of the common carotid artery, respectively. Analysis of all included patients. Measurements adjusted for baseline mean BMI and maximum BMI, respectively, and the time between measurements.

1. The use of a pharmaceutical product containing beta-blocker at a maintenance dose of less than 50 mg, which represents the highest dose of any beta-blocker that blocks beta-1 receptors to the same extent as 47 mg of metoprolol succinate, to reduce the increase of heart rhythm caused by exercise within 24 h, in a mixture with a pharmaceutically acceptable adjuvant, diluent or wear elem in the manufacture of medicaments for prophylactic or therapeutic treatment of atherosclerosis.

2. The use according to claim 1 where the pharmaceutical preparation contains a beta-blocker in a maintenance dose in the range 25-47 mg in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

3. The use according to claim 2, where the dose of beta-blocker 25 mg

4. The use according to any one of claims 1 to 3, where the beta-blocker is a metoprolol, or its stereoisomers, or its pharmaceutically acceptable salt, or MES of such salt.

5. The use according to claim 4, where the beta-blocker is a succinate metoprolol, metoprolol fumarate or tartrate metoprolol.

6. The use according to claim 5, where the beta-blocker is a succinate metoprolol.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for treatment of diseases, associated with alterations of blood extracellular DNA, such as generalized infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. Method includes administering of blood extracellular DNA destroying agent into blood. As such agent DNAase is used, in particular in doses providing alteration of electrophoretic profile of blood extracellular DNA, detectable by pulse gel electrophoresis. DNAase may be administrated in doses and regimes providing exceeded levels of blood plasma DNA-hydrolytic activity, namely 150 Kuntz/l of plasma, during 12 h/day in total.

EFFECT: effective method for treatment of abovementioned diseases without side effects.

4 cl, 14 tbl, 15 ex, 5 dwg

FIELD: medicine, cardiology.

SUBSTANCE: the complex of medicinal therapy includes nibentane to be injected at the dosage of 0.125 mg/kg intravenously. Moreover, one should pre-inject magnesium sulfate solution at the dosage of 2.5 g about 10-15 min before nibentane injection. The innovation provides quick restoration of sinus rhythm in case of no therapeutic complications observed.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, cardiology, biochemistry.

SUBSTANCE: invention relates to benzoyl guanidines of the formula (I): wherein R1 means -CF3; R2 means -Y-para-(C6H4)-R11, -Y-meta-(C6H4)-R11 or -Y-ortho-(C6H4)-R11 wherein R11 means (C1-C9)-heteroaryl comprising two or more nitrogen atoms adjoining across nitrogen (N) atom; Y means oxygen atom; R3 means hydrogen atom; R4 means (C1-C4)-alkyl, and to their pharmaceutically acceptable salts. Indicated compounds elicit very high activity with respect to inhibition of Na+/H+ exchange and improved water solubility and therefore they can be used as anti-arrhythmic medicinal agents with cardioprotective component for prophylaxis of infarction and treatment of infarction and for treatment of stenocardia. Also, proposed compounds inhibit pathophysiological processes in arising disorders induced by ischemia, in particular, in treatment of cardiac arrhythmia induced by ischemia.

EFFECT: improved preparing method, improved treatment and prophylaxis, valuable medicinal properties of compounds.

17 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves applying intracoronary phosphocreatine introduction into infarction-responsible artery when carrying out coronary angioplasty. Phosphocreatine solution is injected after reperfusing the infarction-responsible artery at constant volume rate of 0.1-4 ml/s with introduced phosphocreatine dose being equal to 0.5-4 g.

EFFECT: reduced myocardium necrosis zone; prevented cardiac insufficiency and cardiac rhythm disorders.

4 cl

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: medicine.

SUBSTANCE: method involves administering a combination of an agent reducing cholesterol content in blood and reduced coenzyme Q10 of general formula .

EFFECT: enhanced effectiveness of treatment.

8 cl, 2 tbl

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment of changed gastroenteric contracting capability. The composition comprises tegaserod and co-agent taken among the group including prucaloprid, fluoxetine, fedotosine, baclofen, octreotide, omeprazol and ranitidine. The combination provides attainment of synergetic effect.

EFFECT: improved and valuable medicinal properties of composition.

7 cl, 3 ex

The invention relates to medicine, namely to Phthisiology, and can be used for the treatment of focal and infiltrative tuberculosis of the lungs

The invention relates to the field of pharmaceutical and analytical chemistry and can be used for determination of papaverine, demerol and other alkaloids in medicinal forms

The invention relates to organic chemistry and can find application in medicine

The invention relates to medicine, namely to a new drug for the treatment of various forms of depression, representing a molecular complex of a free base of fluoxetine with glycyrrhizic acid in the following ratio of components: the free base of fluoxetine: glycyrrhizin acid 1:(1-4)
The invention relates to medicine and can find application in the treatment of cardiovascular diseases accompanied by high activity of Pro-inflammatory cytokines

The invention relates to a new methyl-isopropyl[(3-n-propoxyphene)ethyl]amine of formula I, where R1represents n-propyl, R2is methyl, R3- isopropyl, or its pharmaceutically acceptable salts, which have the properties of a topical local anaesthetics and can be used to produce medicines used for local anesthesia

The invention relates to medicine, namely to the treatment of bladder dysfunction caused by hyperactivity of the detrusor

Antiglaucoma tool // 2191013
The invention relates to medicine, in particular to ophthalmology

The invention relates to medicine, namely to funds with beta-adrenoceptor blocking activity and is used in cardiology

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment of changed gastroenteric contracting capability. The composition comprises tegaserod and co-agent taken among the group including prucaloprid, fluoxetine, fedotosine, baclofen, octreotide, omeprazol and ranitidine. The combination provides attainment of synergetic effect.

EFFECT: improved and valuable medicinal properties of composition.

7 cl, 3 ex

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