Renin-angiotensin system inhibitors application for preventing cardiovascular disease manifestations

FIELD: medicine.

SUBSTANCE: method involves administering required dose of renin-angiotensin inhibitor Ramipryl or its salt combined with a hypotensive drug, means for reducing cholesterol content, diuretic or aspirin to patients showing no signs of left ventricle dysfunction or cardiac insufficiency.

EFFECT: prevented cardiovascular attacks, angina pectoris, diabetes manifestations.

18 cl, 5 tbl

 

The scope of the invention

The present invention relates to the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative, optionally together with other antihypertensive agent, lowering cholesterol by means of diuretic or aspirin in the manufacture of a medicine for the prevention of cardiovascular crises; to a method of prevention of cardiovascular crises, including the introduction of a patient in need of such prevention an effective amount of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative, optionally together with other antihypertensive agent, lowering cholesterol by means of diuretic or aspirin; or to the combined product containing the inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative and lowering cholesterol tool.

Background of the invention

The renin-angiotensin system (RAS) can be characterized by the inhibition of enzymes that synthesize angiotensins, or blocking of the receptors in the effective sites. There are many tools that are on sale or on the research phase, which inhibit the activity of RAS, and many m which should be divided into two large classes: inhibitors of angiotensin-converting enzyme (ACE), accepted names usually end in "-app" or, in the case of active metabolites, "Pilat", and antagonists against the angiotensin receptor (more specifically, at present, AT1receptor) (antagonists of angiotensin II), adopted names usually end in "-Sartan". Also potentially increases the value of the class of drugs known as inhibitors of neutral endopeptidase (NEP), which also have ACE-inhibitory activity or the ability of weakening RAS activity, and therefore also known as NEP/ACE inhibitors.

The ACE inhibitors are well known in this field due to their inhibitory activity against angiotensin-converting enzyme than is blocked transformation decapeptides of angiotensin I to angiotensin II. Basic pharmacological and clinical effects of ACE inhibitors are the result of suppression of the synthesis of angiotensin II. Angiotensin II is a strong vazopressornye agent, and therefore the inhibition of its biosynthesis can lead to low blood pressure, especially in animals and in people who have hypertension associated with angiotensin II. The ACE inhibitors have proved to be effective antihypertensive agents in various animal models and in clinical use for the treatment of hypertension in humans.

Ing bitory ACE also used to treat conditions of the heart, such as hypertension and heart failure. It is known that at least some of the ACE inhibitors can improve (i.e. reduce) the morbidity and mortality in patients with conditions such heart, such as low ejection fraction (EF) or heart failure (HF), but their role for a broader group of patients with high risk without ventricular dysfunction or HF is unknown.

The invention

The present invention mainly concerns the application of the inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative for the preparation of drugs for prevention of cardiovascular crises.

The present invention relates also to the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative for the preparation of drugs for prevention of myocardial infarction, worsening of angina and cardiac arrest.

In addition, the present invention relates to the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative for the preparation of drugs for prevention of cardiovascular crises, such as, for example, myocardial infarction, worsening of angina or cardiac arrest in a patient with increasing the military risk of cardiovascular diseases, for example, because of the manifest coronary heart disease, transient ischemic attacks or stroke in history, or peripheral vascular disease in history.

In a more General sense, the present invention relates to the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative for the preparation of drugs for prevention of cardiovascular crises in patients without symptoms of dysfunction of the left ventricle or heart failure.

The present invention further relates to the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative for the preparation of drugs for prevention of myocardial infarction (mi), stroke, cardiovascular death or manifestirovanne nephropathy in a patient with diabetes mellitus.

Another embodiment of the present invention is the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative together with other antihypertensive agent, lowering cholesterol by means of diuretic or aspirin for the preparation of drugs for prevention of cardiovascular crises, such as stroke, congestive heart failure, cardiovascular mortality is, myocardial infarction, worsening of angina, cardiac arrest, or prevention of revascularization procedures.

Another embodiment of the present invention is the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative together with other antihypertensive agent, lowering cholesterol by means of diuretic or aspirin for the preparation of a medicine for the prevention of diabetes or diabetic complications.

The following embodiment of the present invention is the use of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative together with other antihypertensive agent, lowering cholesterol by means of diuretic or aspirin for the preparation of drugs for prevention of congestive heart failure (CHF) in patients not previously suffered congestive heart failure.

Another embodiment of the present invention is a combination product containing an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative and other antihypertensive agents for lowering cholesterol agent, a diuretic or aspirin, for use in the prof is the phenomenon of cardiovascular crises.

Another embodiment of the present invention is a combination product containing an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative and lowering cholesterol tool.

The following embodiment of the present invention is a method of prevention of cardiovascular crises, such as myocardial infarction, worsening of angina and heart failure comprising the administration to a patient in need of such prevention an effective amount of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative, and particularly in patients with an increased risk of cardiovascular disease.

Another embodiment of the present invention is a method of preventing myocardial infarction, stroke, cardiovascular death or manifestirovanne nephropathy in a patient with diabetes mellitus, including the introduction of a specified patient an effective amount of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative.

The following embodiment of the present invention is a method of prevention of cardiovascular crises, such as stroke, congestive heart failure, cardiovascular death, myocardial infarction, worsening of angina, cardiac arrest, or prevent the of piracy revascularization, or diabetes or diabetic complications, comprising the administration to a patient in need of such prevention an effective amount of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative together with an effective amount of another antihypertensive means lowering cholesterol means, a diuretic or aspirin (combination therapy).

Another embodiment of the present invention is a method of preventing congestive heart failure in a patient not previously suffered congestive heart failure, involving the introduction of a specified patient an effective amount of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative together with an effective amount of another antihypertensive means lowering cholesterol means, a diuretic or aspirin (combination therapy).

A detailed description of the invention

Unexpectedly, it was found that cardiovascular crises, such as stroke, congestive heart failure, cardiovascular death, myocardial infarction, worsening of angina, cardiac arrest, or revascularization surgery, such as coronary bypass surgery (CABG), RTCA, peripheral angiola the tick, amputation, carotid endarterectomy and diseases associated with metabolic disorders such as diabetes or diabetic complications, such as manifestirovanne nephropathy, dialysis or laser therapy or newly diagnosed microalbuminuria, using an inhibitor of the RAS system can be prevented from a wide group of patients with high-risk asymptomatic left ventricle dysfunction or heart failure.

In addition, and very unexpectedly, we also observed a prevention of cardiovascular crises in a very wide range of patients with a high degree of risk in addition to other effective treatment, for example, antihypertensive agents (other than inhibitors of the RAS system), diuretics, lower cholesterol means or aspirin.

Thus, the present invention describes a new method for the prevention of cardiovascular crises, including the introduction of a patient in need of such prevention an effective amount of an inhibitor of the renin-angiotensin system or its pharmaceutically acceptable derivative, optionally together with other antihypertensive agent, lowering cholesterol by means of diuretic or aspirin.

Patients with high risk disease are the two who are, for example, patients who have cardiovascular risk of stroke, caused by a manifestation of ischemic heart disease, transient ischemic attacks or stroke in history, or peripheral vascular disease in history. Another group of patients with high risk includes those patients with diabetes mellitus.

The term "diabetes"as used here means as diabetes mellitus type I, also known as insulin-dependent diabetes mellitus (IDMM), and diabetes mellitus type II, also known as non-insulin dependent diabetes mellitus (NIDDM).

The term "diabetic complications", as used here, means manifestival nephropathy, indications for laser therapy or dialysis.

The term "inhibitor of the renin-angiotensin system (RAS) or its pharmaceutically acceptable derivative", as used here, means any compound which by itself or by the insertion blocks the negative effects of angiotensin II on vascular network, either by reducing the synthesis of angiotensin II or blocking its action on the receptor.

Inhibitors of RAS include ACE inhibitors, antagonist of angiotensin II and renin inhibitors and their pharmaceutically acceptable derivatives, including prodrugs and metabolites.

The term "inhibitor of the angiotensin converting enzyme ("ACE inhibitor"means the tool is not the connection or combination of two or more products or compounds, having the ability to block, partially or completely, rapid enzymatic conversion of physiologically inactive Decapeptide forms of angiotensin (Angiotensin I) narrowing the blood vessels octapeptide form of angiotensin (Angiotensin II). The term "ACE inhibitor" also includes so-called inhibitors of NEP/ACE (also referenced as inhibitors of neutral endopeptidase selective or double action), which have inhibitory neutral endopeptidase (NEP) activity and inhibiting angiotensin-converting enzyme (ACE) activity.

Examples of ACE inhibitors suitable for use herein are, for example, the following compounds: AB-103, uncovered, benazeprilat, BRL-36378, BW-A575C, CGS-13928C, CL242817, CV-5975, Equation(Equaten), EU-4865, EU-4867, EU-5476, proximity, FPL 66564, FR-900456, Hoe-065, I5B2, indrapuri, ketomalonate, KRI-1177, KRI-1230, L681176, dibenzepin, MCD, MDL-27088, MDL-27467A, multiperil, MS-41, nicotianamine, pentopril, fencein, pivotal, renipril, RG-5975, RG-6134, RG-6207, RGH0399, ROO-911, RS-10085-197, RS-2039, RS 5139, RS 86127, EN-44403, S-8308, SA-291, spirapril, SQ-26900, SQ-28084, SQ-28370, SQ-28940, SQ-31440, Sincor(Synecor), ulibarri, WF-10129, Wy-44221, Wy-44655 Y-23785, Wissam(Yissum), P-0154, saucepan, Asahi Brewery AB-47, elatioris, BMS 182657, Asahi Chemical C-111, Asahi Chemical C-112, Dainippon DU-1777, missapril, Prantil(Prentye), zofenoprilat, 1-(1-carboxy-6-(4-piperidinyl)hexyl)amino)-1-oxopropionate-1H-indole-2-carboxylic acid is, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, andapril, perindoprilat and Servier S-5590, alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, tainabilit, imidapril, lisinopril, perindopril, inapril, ramipril, ramiprilat, carolinastate, temocapril, trandolapril, trandolaprilat, ceronapril, moexipril, inapril and spirapril.

The group of ACE inhibitors, which are of great interest, is alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilata, imidapril, lisinopril, perindopril, inapril, ramipril, ramiprilat, carolinastate, temocapril, trandolapril, trandolaprilat, ceronapril, moexipril, inapril and spirapril.

Many of these ACE inhibitors are commercially available, especially those listed in the above group. For example, it is highly preferred ACE inhibitor ramipril (known from EP 79022) sold by the company Aventis, for example, under the trademark Delix® or Altace®. Enalapril or Enalaprilat and lisinopril are the two most preferred ACE inhibitors, sold by Merck & Co. Enalapril sold under the trademark Vasotec®. Lisinopril is sold under the trademark Prinivil®.

Included here are examples of inhibitors of NEP/ACE, suitable for the uses described in U.S. patent No. 5508272, 5362727, 5366973, 522540, 4722810, 5223516, 5552397, 4749688, 5504080, 5612359, 5525723, 5430145 and 5679671 and applications for the grant of the European patent 0481522, 0534263, 0534396, 0534492 and 0671172.

Preferred are also inhibitors of NEP/ACE, which are indicated as preferred in the above U.S. patents and European patent applications, and they are included here as a reference. Especially preferred is an inhibitor of NEP/ACE omapatrilat (described in U.S. patent No. 5508272) or MDL100240 (described in U.S. patent No. 5430145).

The terms "antagonist of angiotensin II covers the agent or compound, or a combination of two or more agents or compounds with the ability to block, partially or completely, the binding of angiotensin II by the angiotensin receptor, in particular, AT1the receptor.

Examples of antagonists of angiotensin II, suitable for use herein are, for example, the following connections: Carolinastate, candesartan cilexetil, CGP-63170, EMD-66397, CT-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, tasosartan, telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-81988, BMS-180560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP 167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, stealin, KRI-1177, L-158809, L-158978, L159874, LR B087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ-38970, RWJ-46458, S-8307 and S-8308, capricornian, saralasin, Carmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, CI-996, DMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, solarton and PD-123319.

A group of antagonists of angiotensin II, which is of great interest, is carolinastate, candesartan, cilexetil, valsartan, candesartan, losartan potassium, eprosartan, irbesartan, tasosartan or telmisartan.

Examples of renin inhibitors suitable here for use are, for example, the following connections: Anacreon; RO 42-5892; AND 65317; CF 80794; ES 1005; ES 8891; SQ 34017; CGP 29287; CGP 38560; SR 43845; U-71038; A 62198; And 64662, A-69729, FK 906 and FK 744.

It is clear that the pharmaceutically acceptable derivatives inhibitors of RAS should include physiologically acceptable salts are inhibitors of RAS, it is clear that such physiologically acceptable salt refers to both organic and inorganic salts, such as described in Remington''s Pharmaceutical Sciences (17th Edition, page 1418 (1985)). With regard to physical and chemical stability and solubility for acid groups are preferred among other salts of sodium, potassium, calcium and ammonium; the main groups are preferred among the salts of hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic acid, or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, Mal is inovas acid, fumaric acid, tartaric acid and p-toluensulfonate acid.

Inhibitors of RAS suitable here to use, or their pharmaceutically acceptable derivatives may be used for animals, preferably to mammals, and in particular to humans as an independent pharmaceutical products, in mixtures with one another or in the form of pharmaceutical preparations.

The present invention relates also to pharmaceutical preparations, containing as active ingredient, at least one inhibitor of RAS and/or its pharmaceutically acceptable derivative, in addition to customary pharmaceutically innocuous excipients and auxiliary components, and to their use for the prevention of heart attacks and for the preparation of drugs based on them. The pharmaceutical preparations normally contain 0.1 to 99 percent by weight, preferably from 0.5 to 95% by weight, an inhibitor of RAS and/or its pharmaceutically acceptable derivative. The pharmaceutical preparations can be obtained essentially in a known manner. To this end, the RAS inhibitor and/or pharmaceutically usable derivative, together with one or more solid or liquid pharmaceutical excipients and/or auxiliary components and, if desired, in combination with other Pharma is efticiency active lead compounds in the form suitable for introduction, or in a standard dosage form, which can then be used as a pharmaceutical preparation for the treatment of human or veterinary medicine.

Pharmaceutical preparations that contain a RAS inhibitor and/or pharmaceutically usable derivative, can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred introduction depends on the specific symptoms of the disease. Inhibitors of RAS and/or pharmaceutically usable derivatives can be used here by themselves or together with pharmaceutical auxiliary components as in veterinary medicine and for the treatment of humans.

The specialist in this area is well known on the basis of special knowledge of auxiliary components that are suitable for the desired pharmaceutical preparation. In addition to solvents, celebratum agents, bases for suppositories, auxiliary components for tablets and other active fillers may be used, for example, antioxidants, dispersants, emulsifiers, means for reducing foam, corrigentov, preservatives, soljubilizatory or dyes.

For a form for oral administration the active compound is mixed with suitable for this purpose additives, such as fillers, stabilizers is whether inert diluents, and conventional methods result in suitable for administration forms such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Inert fillers which may be used are, for example, Arabian gum, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, you may be getting both dry and wet granules. Possible oil fillers or solvents are, for example, vegetable or animal fats, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active connection is transferred into a solution, suspension or emulsion, if desired, with the usual substances, such as solubilization, emulsifiers or other accessories. Suitable solvents are, for example: water, physiological saline solution or alcohols, for example ethanol, propanol, glycerol, and optionally also solutions of sugars such as glucose or mannitol, or, alternatively, a mixture of these solvents.

Pharmaceutical preparations suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of formula I in the pharmaceutical and food & the automatic acceptable solvent, such as, in particular, ethanol or water, or in mixtures of such solvents.

If necessary, the preparation can also contain other pharmaceutical auxiliary components, such as surfactants, emulsifiers and stabilizers, as well as the propellant. This product usually contains the active compound in concentrations of from about 0.1 to 10, in particular from about 0.3 to 3% by mass.

The dose of the active connections that you want to enter, and the frequency of introduction will depend on the effectiveness and duration of action of the compounds used; additionally also on the nature and gender, age, weight and individual response of the mammal, which is subjected to treatment in the introduction.

The average daily dose for a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg to about 20 mg/kg, preferably 1 mg/kg, of body weight.

Inhibitors of RAS and/or pharmaceutically usable derivatives can also be used to achieve successful therapeutic effect together with other pharmacologically active compounds for the prophylaxis of the above symptoms.

The present invention also relates to the combined product containing the inhibitor of the renin-angiotensin system or its pharmaceutical is acceptable derivative and other antihypertensive agents, lowering cholesterol agent, a diuretic or aspirin, for use in the prevention of cardiovascular crises.

The invention also relates to the combination of a RAS inhibitor and/or its pharmaceutically acceptable derivative with lowering cholesterol means.

In addition to the introduction in the form of a combination of a particular composition, the invention also relates to the simultaneous, separate or sequential introduction of the RAS inhibitor and/or its pharmaceutically acceptable derivative with another antihypertensive agent, lowering cholesterol by means of diuretic or aspirin.

The invention also relates to a pharmaceutical preparation containing a RAS inhibitor and/or its pharmaceutically acceptable derivative and lowering cholesterol means (combination product).

Pharmaceutical combination product according to the invention can be obtained, for example, either by intensive mixing of the individual components in the powder, or by dissolving the individual components in an appropriate solvent, such as, for example, lower alcohol, and subsequent removal of solvent.

The mass ratio of the RAS inhibitor and/or its pharmaceutically acceptable derivative and down with the holding of cholesterol funds in new combinations and preparations is in the range from 1:0.01 to 1:100, preferably from 1:0.1 to 1:10.

New combinations and drugs in General may contain from 0.5 to 99.5% by weight, in particular 4-99% by weight, of these active compounds.

When using, according to the invention, for mammals, preferably humans, doses of different active ingredients compounds, for example, vary from 0.001 to 100 mg/kg/day.

As a rule, the individual daily doses of these combinations can be from about one to five minimum recommended clinical doses up to the maximum recommended levels for objects in a single implementation.

Through the combined introduction one component of the combination may be enhanced by other appropriate component, that is, the action and/or duration of action of a new combination or mixture is stronger or longer lasting than the action and/or the duration of the respective individual components (synergistic effect). When combined introduction this leads to dose reduction of the corresponding component of the combination compared with the introduction of separately. New combinations and preparations, respectively, have the advantage that the number of active connections that you want to enter, can be significantly reduced, and undesirable side affectyour be eliminated or significantly reduced.

The preferred combination product combinations could include, for example, as inhibitors of the RAS alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilata, imidapril, lisinopril, perindopril, inapril, ramipril, ramiprilat, carolinastate, temocapril, trandolapril, Trandafirilor, ceronapril, moexipril, FinePrint or spirapril, most preferably ramipril, as lowering cholesterol means lovastatin, pravastatin, simvastatin or fluvastatin.

The term "combination therapy", in defining use of an inhibitor of the RAS system together with other antihypertensive agent, lowering cholesterol by means of diuretic or aspirin, implies the introduction of each tool in sequence mode, which will ensure the successful action of a combination of drugs, and also includes co-administration of these funds, essentially simultaneously, such as ingestion of agents one capsule with a certain ratio of these active agents or in multiple swallowing multiple, separate capsules for each agent.

"Combination therapy" will also include simultaneous or sequential introduction of intravenous, intramuscular or other part realname ways in the body, including direct absorption through mucous membrane tissues, as detected in the coronary sinus passages. Sequential introduction also includes a combination of drugs, where the individual elements can be introduced at different times and/or in different ways, but which act in combination to provide a favourable effect.

The term "effective amount" means a certain amount of each agent for use in combination therapy, which provides a goal for the prevention of heart attacks and thus avoids the adverse side effects normally associated with each agent.

Examples of other classes of antihypertensive agents for use in the product combination or used in combination therapy include, for example, calcium channel blockers or calcium antagonists and beta-blockers.

Used beta-blockers include timolol, atenolol, metoprolol, propanolol, nadolol and endolaryngeal.

Used calcium channel blockers include diltiazem, felodipine, nifedipine, amlodipine, nimodipine, isradipine, nitrendipin, and verapamil.

Used diuretics include methyclothiazide, hydrochlorothiazide, torsemide, metolazone, furosemide, chlorthalidone, N-(5-sulfamoyl-1,3,4-thiadiazole-2-yl)ndimethylacetamide, t is interen, chlorothiazide, indapamide, bumetanide, amiloride, spirolactone, bendroflumethiazide, benzthiazide, cyclothiazide, jinitiator, hydroflumethiazide, polythiazide, trichlormethiazide and etakrinova acid.

The example used to lower blood cholesterol drugs are the statins.

The conversion of 3-hydroxy-O-methylglutaryl-coenzyme A (HMGCoA) mevalonata is primary and determines the speed stage in the biosynthetic pathway of cholesterol. This stage is catalyzed by the enzyme Nmoaa reductase. Statins inhibit HMGCoA reductase from this catalytic conversion. Essentially, statins are powerful collective lower cholesterol means.

Statins include such compounds as simvastatin, is described in U.S. patent 4444784, pravastatin, described in U.S. patent 4346227, tseriwastatina described in U.S. patent 5502199, mevastatin described in U.S. patent 3983140, melastatin described in U.S. patent 4448784 and in U.S. patent 4450171, fluvastatin, described in U.S. patent 4739073, compactin described in U.S. patent 4804770, lovastatin, described in U.S. patent 4231938, dalvastatin described in EP-A-738510, plugindomain described in EP-A 363934, atorvastatin, described in U.S. patent 4681893, atorvastatin calcium, is described in U.S. patent 5273995, and dihydrocoumarin described in U.S. patent 4450171, all the above-mentioned document what you included here as a reference.

Preferred statins include lovastatin, pravastatin, simvastatin and fluvastatin.

Aspirin irreversibly inactivates platelet cyclooxygenase by acetylation of the enzyme at the active site. In addition to reducing mortality, aspirin also reduces the risk of stroke and myocardial infarction. The exact mechanisms of successful action of aspirin is not known.

Examples

The examples described here are intended to illustrate various aspects of the implementation of the present invention and are not intended to limit the invention in any way.

Large-scale clinical trials (HOPE(Heart Outcomes Prevention Evaluation)Study was designed to study the validity of the ACE inhibitor ramipril compared with placebo on the reduction of cases of cardiovascular crises. 9297 patients with high risk (≥ 55 years of age with evidence of vascular disease or diabetes plus one additional risk factor) without known low EF or HF were randomized to receive Ramipril (Ramipril) (from 2.5 mg to 10 mg/day) or matching placebo in a period of time equal to an average of 5 years. The primary outcome was the first case of cardiovascular (CV) death, myocardial infarction or stroke. The study was stopped after 4.5 years in accordance with the independent data and Safety Monitoring Board because of the convincing evidence of the success of the treatment. At 646 (13,9%) of patients treated with ramipril and 816 (17,5%) patients receiving placebo differed primary outcome (relative risk RR=0,78, confidence interval=95% 0,70-0,86; Portable=0,000002). There were obvious and significant reduction of indicators separately for CV mortality (6.0 percent versus 8.0%, RR of 0.75, Portable=is 0.0002), myocardial infarction (9,8% compared to 12.0%, RR of 0.68, Portable=is 0.0002). Secondary outcomes such as overall mortality rate of 10.3% versus 12.2%, RR 0,00035), operations revascularization (16,0% compared to 18.4%, RR of 0.85, Portable=0,0013), cardiac arrest (of 0.8% vs 1.2%, RR was 0.63, Portable=0,03), heart failure (7,4% vs. 9.4%, RR 0,78, Portable=0,0005) and diabetic complications (6,4% vs. 7.7%, RR of 0.85, Portable=0,017), were also significantly reduced. Other results included worsening or new discovery angina, or new detection of heart failure (regardless of hospitalization).

Ramipril significantly reduces mortality, myocardial infarction, stroke, prevents operation of revascularization and heart failure, and prevents diabetic complications in a large group of patients with high risk without low EF or heart failure.

The protocols and results described in the examples presented here below.

Example 1

The plan of study

In a double-blind, 2×2 factorial, randomized HOPE evaluated ramipril or Vita is in E in 9541 patients. In pozyskiwanie on 244 patients studied the effect of low-dose (2.5 mg/day) compared with full-dose (10 mg/day), Ramipril. The primary result of these 244 patients recorded as notes to table 3. Thus, the report on the main results are presented for 9297 patients randomized to receive 10 mg Ramipril or equivalent placebo. About the effects of vitamin E reported separately. The plan HOPE was published (Can J Cardiology 1996; 12 (2); 127-137), a brief summary follows below.

Inclusion/exclusion patient

Selected men and women, whose age is equal to 55 years and older with prior coronary artery disease, stroke, peripheral vascular disease or diabetes and at least one other risk factor (current or previous hypertension, elevated total cholesterol, low HDL cholesterol, constant Smoking cigarettes, known microalbuminuria or previous vascular disease). Patients who had HF, as it is known, should have a low EF, those who took an ACE-I or vitamin E, with uncontrolled hypertension or manifestirovanne nephropathy, or recent MI (<4 weeks) were excluded. On this scale, a simple experiment was impractical to assess left ventricular function in all patients (except those who had heart failure or in need of ACE-I). Instead of echocardiograms were performed in all patients (n=496) of the 3 groups that were included in pozyskiwanie. At 2.6 per cent, it was found that EF<0,40. Additionally, checking maps showed that 5285 patients were pre-randomization and assessment of ventricular function. Only 409 (7,7%) were in low EF, and none had heart failure before randomization. Provided a separate analysis of those registered who had constant EF (n=4876). Upon receipt of written notification of the consent of all selected patients entered a phase when they took 2.5 mg of Ramipril OD for 7-10 days and then the corresponding placebo within 10-14 days. Patients who did not observe mode (took <80% of pills), who observed side effects with advanced pathological levels of creatinine or potassium, or those who withdrew consent were excluded. 9541 were included; 9297 were randomized to receive Ramipril 10 mg/day or matching placebo, and 244 randomized to low-dose (2.5 mg/day), Ramipril.

At randomization, patients were assigned to receive Ramipril 2.5 mg OD for one week, then 5 mg OD in the next 3 weeks and then 10 mg once daily or matching placebo. In addition, all patients were randomized to vitamins to anti scar is on E 400 IU/day or matching placebo. Follow-up visits occurred at 1 month, 6 months and then 6-monthly intervals. Every visit to collect data on the events, conditions and side effects, leading to change of the investigational treatment. All primary and secondary events were recorded to additional forms and centrally installed using the standard wording.

Organization of the study: patients were recruited over an 18-month period (from December 1993 to June 1995) of the centers in Canada (129), USA (27), 14 Western European countries (76), Argentina and Brazil (30) and Mexico (5). The expert Council of each institution has accepted the Protocol. The study was organized and coordinated by the Canadian Cardiovascular Collaboration Project Office, located in Preventive Cardiology and Therapeutics Research Program, Hamilton Health Science Corporation Research Centre, McMaster University, Hamilton, Canada. Additional offices were in London, England; Sao Paulo, Brazil, and Rosario, Argentina. Responsibility for the overall study was undertaken by the Preparatory Committee.

Statistical analysis: the study was originally developed for the participants for an average period of 3.5 years. However, before the end of this period, the Preparatory Committee (all results are obtained blind) approved a possible sequel to until treatment n who will give their full effect and recommended to extend the period up to 5 years. Taking the speed of the stroke, equal to 4% annually for 5 years, 9000 patients, we would have 90% power to detect a 13.5% relative risk reduction using 2-sided alpha of 0.05, analyzed for treatment reasons. Survival curves were estimated using the method of Kaplan-Meier and compared treatment using the Protocol of consecutive measurements. Because of the factorial plan of the experiment all studies were stratified for randomization to vitamin E or control. Cubonova analysis was carried out using research cooperation on the Sokh regression model. This model was also used to estimate the treatment effect is determined for any imbalance in key prognostic factors. Installed and uninstalled analyses provided virtually identical results, therefore, provided only unidentified evaluation.

Interim analysis, the data control and early completion: the independent data and secure information Board (DSMB) monitored the course of all aspects of the study. There were four scheduled formal interim study. Statistical boundary control for success requires the crossing of four tolerance for the first half of the experiment and three tolerance in the second half. For harm is suitable the border was three and two deviations, respectively. The decision to stop or continue the experiment would depend on the number of additional factors, including the status of results among key subgroups. 22 March 1999 independent DSMB recommended termination of the experiment because of the obvious and permanent confirm the benefits of Ramipril, which had a consistent and clear the intersection controlled borders in two successive species (20% relative risk reduction in the primary outcome with 95% CI 12% to 28%, Z - 4,5; p=0.00001). The experimental results were announced researchers at two meetings held on April 17 and April 24. Termination for all cases for the primary analysis was appointed on 15 April 1999. Recent receptions held from 19 April and planned to be completed until June 30, 1999.

Example 2

Patient characteristics

Table 1 presents baseline characteristics of patients participating in the study. Noted that it was 2480 women (26.7 percent), 5128 person > 65 years (55.2 per cent), 8160 with coronary artery disease (87,8%), 4355 diagnosed with hypertension (46,8%) and 3578 with diabetes (38,5%). It makes the most extensive study of ACE-I on women, the elderly and among diabetics and a large number of hypertensive patients with a high degree of risk.

Example 3

Mode

Distributed in groups is receiving Ramipril share affected by the research or open-label ACE-I was 87.4% in 1 year to 85.2% in the 2nd year, 82.2% in year 3, and 75.5% in year 4 and 78.3% at the last visit. 82,9% took 10 mg of Ramipril in 1 year, 74.8 per cent in year 2, 71.0% of the 3 year, 62.8% in year 4 and 64,6% at the last visit. Distributed for placebo, the proportion of open-label ACE-I was 3,4%, 6,0%, 8,1%, 10,7% and 12.7%, respectively. At the final stage of the study 1.6% of patients taking Ramipril, and 1.9% of patients treated with placebo, took receptor antagonist angiotensin-2. The most common causes for interruption-blind treatment drug highlighted in Table 2. The majority of patients in the group taking Ramipril stopped taking drugs cough (7,2% vs. 1.7%) or hypertension (1.8 percent vs. 1.4 percent). For comparison, the majority of patients receiving placebo, stopped-blind treatment with untreated hypertension (0,3% against 0.6%) or clinical stroke (of 1.9% vs. 2.4%). The proportion of patients receiving unexplored ACE-I against heart failure, was equal to 3.3% in the active group and 4.5% in the group receiving placebo, against proteinuria was equal to 1.4% from 1.6% and for the treatment of hypertension of 4.4% versus 6.2%. The use of open-label And-2 receptor antagonists in both groups was low (1.6 percent vs. 1.9 percent), but the reasons reflect the characteristics similar to the use of ACE-inhibitors (heart failure, or 0.6% vs. 0.8%, hypertension 1.1 percent versus 1.3 percent).

Table 2
Causes interrupt blind treatment
RamiprilPlacebo
No. randomized46454652
No. terminated at any time*1370 (33,0)1247 (30,7)
No. Constantly stopped*1207 (29,1)1087 (26,7)
Reasons for termination
Cough335 (7,2%)81 (1,7%)
Hypotension/dizziness82 (1,8%)65 (1,4%)
Disease Quincke16 (0,3%)12 (0,3%)
Unmanaged hypertension16 (0,3%)30 (0,6%)
Clinical crises90 (1,9%)113 (2,4%)
Unexplored ACE-I124 (2,7%)187 (4,0%)
The reasons for using open-label ACE-I
Heart failure231 (5,0%)320 (6,9%)
Proteinuria63 (1,4)73 (1,6%)
Hypertension205 (4,4%)289 (6,2%)
* % living

Example 4

Blood pressure

Initially BP was equal 139/79 in both groups. It decreased to 133/76 in the active group and to 137/78 in the control group at 1 month, 135/76 and 138/78 after 2 years and 136/76 and 139/77 at the final stage of the study.

Example 5

Main results and total mortality (table 3)

Of the 646 patients in the group receiving Ramipril (13,9%) underwent CV death, MI or stroke, relatively 816 (17,5%) in the placebo group (RR to 0.78, 95% CI 0.70 to 0,86; p=0,000002). In addition, there were significant reductions separately CV mortality (278 vs. 371, RR of 0.75, 95% CI of 0.64 to 0.87; p=0.0002), MI (453 vs. 559, RR of 0.80, 95% CI of 0.71-of 0.91; p=0.0005) and stroke (155 vs. 225, RR of 0.68, 95% CI 0.56 to 0,84; p=0.0001). The number of causes of death was also significantly reduced (476 vs. 567, RR of 0.83, 95% CI of 0.74-to 0.94; p=0,0035).

CV death
Table 3: Main results and his performance in

the experiment HOPE
RamiprilPlaceboRRR (95% CI)ZLogarithmic number R
No.46454652
CV death, stroke646 (13,9)816 (17,5%)0,78(0,70-0,86)-4,750,000002
278 (6,0%)371 (8,0%)0,75(of 0.64 to 0.87)-3,72is 0.0002
THEM453 (9,8%)559 (12,0%)0,80(0,71-0,91)-3,490,0005
Strokes*155 (3,3%)225 (4,8%)of 0.68(0.56 to 0,84)-3,70is 0.0002
Total mortality476 (10,3%)567 (12,2%)0,83(0,74-0,94)-2,920,0035
* additional 34/244 crises with a low dose of Ramipril. The inclusion of these crises will lead to 13.9% major crises with Ramipril relative to 17.5% with placebo (RRR to 0.78, 95% Cl 0,70-0,86). Note that patients may have experienced more than one crisis.

Example 6

Additional and other results (table 4)

There was a significant reduction in the number of patients undergoing revascularization procedures (742 against 854, RR of 0.85, 95% CI 0.77-a to 0.94; p=0,0013), and a tendency to decrease the number of HF hospitalizations (150 versus 176; RR is 0.84, 95% CI of 0.68-to 1.05; p=0.13). But was not given any action regarding the number of hospitalizations of patients with unstable angina. There was also a significant reduction in the number of patients with heart stops (37 vs. 58, RR=0,63, p=0.03), worsening angina (1104 against 1220, RR=0,88, p=0.00), new heart failure (343 against 435, RR=0,78, p=0.0005), new diagnosis of diabetes (108 157 against, RR=0,69, p=0.003), or experiencing diabetic complications (319 against 378, RR=0,85; p=0,018).

Table 4
Additional and other results of the experiment HOPE
RamiprilPlaceboRRR (95% CI)ZLogarithmic number R
No.46454652
Additional results
Revascularize*742 (16,0%)854 (18,4%)0,85

(0,77-0,94)
-3,220,0013
Hospitalized with unstable angina*564 (12,1%)573 (12,3%)0,98

(0,87-1,10)
-n.s.
Diabetic complications + *298 (6,4%)357 (7,7%)0,83

(of 0.71 to 0.97)
-2,390,017
Hospitalization with heart failure*150 (3,2%)176 (38%) 0,84

(0,68-1,05)
-1,530,13
Other results
All cases of heart failure **343 (7,4%)435 (9,4%)0,78

(0,67-0,90)
-3,510,0005
Cardiac arrest37 (0,8%)58 (1,2%)0,63

(0,42-0,96)
-2,190,03
Worsening angina**1104 (23,8%)1220 (26,2%)0,88

(0,81-0,96)
-2,980,0029
A new diagnosis of diabetes mellitus108 (3,8%)157 (5,5%)0,69

(0,54-0,88)
-3,010,0026
UA with ECG changes179 (3,4%)185 (4,0%)0,96

(0,78-1,18)
-n.s.
Registered crises ** include cases regardless of hospitalization. + diabetic complications, including diabetic nephropathy, dialysis and laser therapy for diabetic retinopathy.

Example 7

Analysis of subgroups (table 5)

A positive effect on the primary outcome was consistently observed in patients patients and no pain what's diabetes; women and men with signs of vascular disease and those up to 65 years and older, with and without hypertension at an early stage and with and without microalbuminuria at the initial stage. Additionally, there were obvious benefits for both groups of patients included in the study, with or without evidence of coronary artery disease, with and without THEM and among those (n=4676), who noted EF>0,40 (317/2339 against 427/2337, RR to 0.73, 95% CI 0,63-0,84, p=0,00002).

Example 8

Time efficiency

The decrease was primarily the result was evident within 1 year after randomization (167 against 197, RR of 0.85; 95% CI 0,69-1.04 million) and became statistically significant after 2 years (323 against 396; RR 0,81; 95% CI 0.70 to 0,94). Due to the survival to the previous year, the relative risk in the second year was equal to 0.78, in the third of 0.74, and 0.73 in the fourth year.

Investigation

The experiment HOPE finally confirms that Ramipril, an ACE-I is useful for a large range of patients without evidence of LV systolic dysfunction or HF who have a high risk of future cardiovascular crises. There are obvious reduction in each of the cases of death, mi and stroke. Coronary revascularization, cardiac arrest and heart failure also obviously reduced. Ramipril also reduces the risk of diabeticheskih complications and the development of diabetes among adiabatical.

Wider dissemination of the useful action of ACE-I at the present time

These data significantly increase the number of those who could benefit from ACE-I and complement previous knowledge about patients with low EF or HF and acute THEM. The main rationale of the study HOPE was that ACE inhibition prevents crises, which were related to ischemia and atherosclerosis, in addition to heart failure and dysfunction of the left ventricle. Avoiding possible confusion in interpreting the results of this study, the authors deliberately limited his experiment patients without HF and removed with known low EF. The study included, however, a large number of individuals at risk of receiving results associated with the progression of atherosclerosis and thrombotic vascular occlusion. Thus was included a wide range of patients with any manifestation of coronary artery disease (e.g. unstable angina, stable angina, or previous revascularization), cerebrovascular diseases in history or peripheral artery disease. As a result, the authors were able to demonstrate the value of ACE-I on a wide range of patients with a variety of clinical manifestations of atherosclerosis, which increases the risk of CV death, mi, or stroke. This method is neither major nor on the additional prevention, but is to a certain extent, prevention strategy high degree of risk, which likely includes individuals with a high probability of a future crisis than includes patients solely on the presence of a particular risk factor or event specific cardio-vascular stroke. These results testify to the success of this method in identifying patients with high risk with significant CV endpoints, are likely to benefit from therapy prevents the progression of atherosclerosis or its complications. These data along with data from the previous experiments have important clinical significance and indicate that documentary evidence of low EF on HF should not be a criterion for the use of ACE-I in the long term in patients with high-risk CV crises at the expense of other clinical criteria.

There were 3578 patients with diabetes included in the study, 1100 of them had no clinical manifestations of CVD and their risk of CV outcomes was lower by about half. Despite this, RRR, we saw, was compatible with the overall beneficial effect in the experiment, and these diabetics comprehensive outcome CV death, stroke, cardiac arrest, revascularization and diabetic complications was signicantly reduce the Yong.

Useful actions of ACE-I, like other preventive methods

The magnitude of the efficiency of ACE-I was, at least, the same as was observed with other additional methods of prevention, such as beta-blockers (Yusuf S et al., Prog Cardiovasc Dis 1985; 27 (5): 335-371), aspirin (BMJ 1994; 308 (6921): 81-106) and a fat burner (Law M. Lipids and cardiovascular disease. Chpt 13 In: Yusuf S, Cairns JA, Camm AJ, Fallen EL, Gersh BJ. (Eds), Evidence-Based Cardiology. London: BMJ Books, 1998. PG. 191-205) during the 4-year treatment period. This wide range of patients HOPE and previous experiments (ACE-I is a very convincing proof of the efficiency in addition to other effective therapies and high portability, ACE-I plays a major role in CV prevention and treatment. The relative risk reduction in the first year of the experiment was approximately 11%, increasing to 22% (conditional expression RRR) in the 2nd year, 26% in the 3rd year and 27% in the 4th year. These data indicate very rapid emergence of efficiency with increasing divergence in the second year, which at least saved and will probably increase in future years. This means that the beneficial action of ACE-I, probably, will be permanent and will probably increase for a longer period of time of treatment.

Useful actions are additional to the accompanying audited medicines

Useful actions Ramipril viewers who were patients receiving a number of effective drugs, such as aspirin, beta-blockers and fat burners, showing that inhibition of ACE offers an additional way to prevent atherothrombotic complications. Only a small portion of abbreviations CV of death, mi and stroke could be attributed to the decrease in BP, since most of the patients participating in the study did not suffer from hypertension (standard definition) and the difference in the reduction of BP was extremely moderate (-3 systolic/-2 diastolic millimeters of mercury). A reduction of 2 mm at lower diastolic BP could at best explain about half of the cuts strokes, and about one-quarter reductions in myocardial infarction (R. Collins et al., Lancet 1990; 335(8693): 827-838). However, recent experiments, such as Hypertension Optimum Treatment (Hansson L. et al., Lancet 1998; 351 (9118): 1755-1762) show that for patients with high risk, such as diabetics, it can be useful for lowering BP even within the "normal" deviations. In addition, a recent re-analysis of the Framingham Heart Study, based on 20 years of data BP (Clarke, R. et al., Am J Epidemiology 1999; 150 (4): (In press)showed that the level of efficiency expected from lower BP may have been underestimated. Despite these considerations, it is possible that more direct mechanisms of ACE-I on the heart or vascular Seth who mattered. They include opposition to direct action of angiotensin II vasoconstriction, proliferation of smooth muscle cells of blood vessels (Lonn EM, et al., Circulation 1994; 90(4): 2056-2069) and destruction of platelets (Schieffer C. et al., Circulation (in press)), improve the function of the vascular endothelium, reduction of LV hypertrophy and increased fibrinolysis (Lonn Em, et al., Circulation 1994; 90 (4): 2056-2069).

We also observed a reduction in the number of patients with the development or hospitalized due to heart failure in patients without evidence of deterioration of LV systolic function. These data complement the SOLVD prevention experiment in patients with low EF and SAVE experiments (low EF early post-MI), who showed that ACE-I prevents the development of heart failure; and experiments on the patients registered with low EF and HF, which showed a reduction in the number of hospitalizations due to heart failure. HOPE these studies suggest that ACE-I, probably, will be assessed patients with high risk of development of heart failure regardless of the degree of systolic dysfunction of the left ventricle. One issue that must be considered is the degree to which the results can be affected by the inclusion of patients with undiagnosed low EF. It will probably be very low, because: a) extensive additional research is in 3 centers includes 468 ordered patients, showed that only 2.6% had EF below 0,40; (b) extensive study card set only <5% of patients with low EF before randomization; and (C) the apparent beneficial effect (RR to 0.73, 95% CI 0,63-0,84; p=0 00002) was observed in the subgroup of patients (n=4676) marked with persistent ventricular function and in patients without prior MI (RR of 0.79, 95% CI 0,69-of 0.90; p=0,0004)

Possible mechanisms of efficiency in diabetes mellitus

Observed a marked reduction in the number of patients developing diabetic complications and the number of newly diagnosed as diabetes. These results can be mediated improvement in insulin sensitivity or reduce hepatic clearance of insulin. The results are also consistent with the results of the recent Captopril Preventoion Project experiment (Hansson L. et al., Lancet 1999; 353 (9153): 611-616), which showed a reduction in the number of patients with recently diagnosed diabetes mellitus in a randomized to captopril compared with diuretic or beta-blocker, and other experiments showing that the progression of diabetic nephropathy in diabetics of type II, taking the ACE inhibitor-I, reduced (Ruggenenti P. et al., Lancet 1999; 354 (9176): 359-364).

Safety and tolerability

ACE inhibitor Ramipril is usually well tolerated by experimente. In addition to increasing the number of patients stopped taking Ramipril from coughing (exceeding 5%), no other side effect not met much more often. There was a slight increase in the number of patients who stopped taking the drug because of dizziness/hypotension (0.3 percent). The majority of patients (approximately 80%) continued to receive ACE-I during 4,2-year duration of the experiment.

Conclusion

The HOPE study clearly shows that Ramipril, long-acting inhibitor of ACE-I reduces mortality, stroke, frequency, revascularization procedures, heart, newly diagnosed heart failure, and diabetic complications in a wide range of patients with a high degree of risk. The introduction of 1000 patients inhibitors ACE-I for 4 years saved 160 patients from the onset of any of the above crises.

The contents of all patents, patent applications, published articles, books, manuals and papers mentioned here, incorporated herein fully by reference to more fully describe the state of the art to which the invention relates.

Since various changes may be made in the above described object without departing from the scope and essence of the invention, this means that the whole structure of the object contained in the above description, reflected in the accompany is their drawings or defined in the additional items interpreted as descriptive and illustrative, and not in the sense of limitations. Various possible modifications and variations of the present invention in light of the above teachings. Therefore, it should be clear that within the additional items, the invention may be made otherwise than in the description.

1. The use of ramipril or its pharmaceutically acceptable salt for the manufacture of a medicinal product for preventing or reducing the risk of stroke, cardiovascular death or myocardial infarction in a patient exposed to cardiovascular risk and without signs of left ventricle dysfunction or heart failure.

2. The use of ramipril or its pharmaceutically acceptable salt for the manufacture of a medicinal product for preventing or reducing the risk of angina, cardiac arrest, or revascularization procedures in patients exposed to cardiovascular risk and without signs of left ventricle dysfunction or heart failure.

3. The use according to claim 2, characterized in that the operation of revascularization is a bypass coronary artery, percutaneous catheter to coronaroplasty, peripheral angioplasty, amputation or endarterectomy in the carotid arteries.

4. The use according to any one of claims 1 to 3, characterized in that, for example, is over the patient's cardiovascular risk is the result of manifestirovanne coronary heart disease, transient ischemic attacks or stroke in history, or peripheral vascular disease in history.

5. The use according to any one of claims 1 to 4, characterized in that the patient suffers from diabetes.

6. The use of ramipril or its pharmaceutically acceptable salt for the manufacture of a medicinal product for preventing or reducing the risk of early diabetes in patients exposed to cardiovascular risk and without signs of left ventricle dysfunction or heart failure.

7. The use according to claim 6, characterized in that diabetes is an insulin-dependent diabetes mellitus (type 1 diabetes).

8. The use according to claim 6, characterized in that diabetes is an insulin-independent diabetes mellitus (type 2 diabetes).

9. The use according to any one of claims 1 to 8, characterized in that the patient has at least one risk factor, which represents the present in the present, or known history of hypertension, elevated total cholesterol, low HDL cholesterol, Smoking at the present time, diagnosed with microalbuminuria or known history of vascular disease.

10. The use according to any one of claims 1 to 9, characterized in that the patient does not suffer from hypertension.

11. The use according to any one of claims 1 to 10, characterized in that the patient is over 55 years of age.

12. The way to prevent or reduce the risk of angina, cardiac arrest, stroke, cardiovascular death, myocardial infarction or revascularization procedures in patients exposed to cardiovascular risk and without signs of left ventricle dysfunction or heart failure, involving the administration of an effective amount of ramipril or its pharmaceutically acceptable salt together with an effective amount of another antihypertensive means lowering cholesterol means, a diuretic or aspirin.

13. The method according to item 12, wherein the antihypertensive agent is a calcium channel blocker or beta-blocker.

14. The method according to item 12, wherein the ramipril or its pharmaceutically acceptable salt is used in combination with lowering cholesterol means.

15. The method according to item 12, characterized in that lowering cholesterol agent is a statin.

16. The method according to item 15, wherein the statin is lovastatin, pravastatin, simvastatin or fluvastatin.

17. The way to prevent or reduce the risk of early diabetes in patients exposed to cardiovascular risk and without signs of left ventricle dysfunction or heart failure, involving the administration to a patient in need of such prevention, an effective amount of ramipril or its pharmaceutically acceptable salt together with an effective amount of the statin.

18. The method according to 17, wherein the statin is lovastatin, pravastatin, simvastatin or fluvastatin.



 

Same patents:

FIELD: medicine.

SUBSTANCE: method involves administering Eucanol at a daily dose of 3-4 g and Ispradin at a daily dose of 1.2-1.3 mg twice a day. Eucanol is taken during a meal and Ispradin is taken 30-40 min before meals.

EFFECT: enhanced effectiveness of treatment; reduced drug consumption.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutically acceptable salts of 2,4,6-trimethyl-2-hydroxypyridine with lower dicarboxylic acids of the general formulae (1-a-d): possessing an antioxidant activity wherein X means a simple bond (compound 1a), oxalate, C8H11NO x C2H2O4; X means -CH2 (compound 1b), malonate, C8H11NO x C3H4O4; X means -CH2-CH2 (compound 1c), succinate, C8H11NO x C4H6O4); X means the group -CH2CH(OH) (compound 1d), malate, C8H11NO x C4H6O5. Also, invention relates to a pharmaceutical composition of salt of the formula (1c) possessing geroprotecting and anti-ischemic activities, and to a method for preparing these salts.

EFFECT: improved preparing method, valuable medicinal properties of substances and pharmaceutical composition.

3 cl, 5 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: method involves additionally administering vitamins B6, B12 and folic acid to patients receiving anticoagulation therapy. Protein content is limited in daily food allowance to 0.8-1.1 g/kg of body weight and cysteine content is increased to 400-500 mg/day.

EFFECT: enhanced effectiveness of treatment; eliminated homocysteine link in pathogenesis.

FIELD: medicine.

SUBSTANCE: method involves administering Clonidine (Clophelinum). The drug is introduced intramuscularly, intravenously or as pills on the background of neurotropic therapy at a dose of 2.5-3.0 mcg/kg of body weight during the first hours of posttraumatic period within 7-10 days.

EFFECT: accelerated and simplified treatment course.

1 dwg, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: invention proposes an agent for correction of abdominal complications in acute period in myocardium infarction. Proposed agent represents ondansetron or domperidone. Agent reduces frequency of hyperemia occurring, improved indices of intestine contractions, promotes to declining lethality in acute period in myocardium infarction.

EFFECT: improved and valuable medicinal properties of agent.

4 tbl, 6 dwg

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

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

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, pharmacology.

SUBSTANCE: invention relates to using the natural triterpenoid of the lupan order, namely betulin, as a capillary-restorative agent. It was found capillary-restorative properties of 1% alcoholic solution of betulin being without its toxic effect on organism. Betulin as 1% alcoholic solution decreases penetrability of mouse skin vessels by 2 times more effective as compared with the known capillary-restorative agent dihydroquercetin. The new agent can be used in treatment of many diseases.

EFFECT: valuable medicinal properties of agent.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves administering Eucanol at a daily dose of 3-4 g and Ispradin at a daily dose of 1.2-1.3 mg twice a day. Eucanol is taken during a meal and Ispradin is taken 30-40 min before meals.

EFFECT: enhanced effectiveness of treatment; reduced drug consumption.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutically acceptable salts of 2,4,6-trimethyl-2-hydroxypyridine with lower dicarboxylic acids of the general formulae (1-a-d): possessing an antioxidant activity wherein X means a simple bond (compound 1a), oxalate, C8H11NO x C2H2O4; X means -CH2 (compound 1b), malonate, C8H11NO x C3H4O4; X means -CH2-CH2 (compound 1c), succinate, C8H11NO x C4H6O4); X means the group -CH2CH(OH) (compound 1d), malate, C8H11NO x C4H6O5. Also, invention relates to a pharmaceutical composition of salt of the formula (1c) possessing geroprotecting and anti-ischemic activities, and to a method for preparing these salts.

EFFECT: improved preparing method, valuable medicinal properties of substances and pharmaceutical composition.

3 cl, 5 tbl, 6 ex

FIELD: pharmacy, chemical technology.

SUBSTANCE: invention relates to methods for preparing simvastatin of high purity degree from lovastatin by the following stages: (a) opening lactone ring in addition of lovastatin in reaction with amine for formation of amide; (b) protection of 1,3-diol moiety by a protecting group; (c) removal of 2-methylbutyryl group joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining of 2,2-dimethylbutyrate group by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and lactone ring closure resulting to formation of simvastatin. Semi-synthetic statin is prepared from statin by carrying out the following steps: (a) opening lactone ring by reaction of statin with amine resulting to formation of amide; (b) protection of 1,3-diol moiety by using the protecting group; (c) removal of group R1 joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining group R2 by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and (g) lactone ring closure with formation of semi-synthetic statin. Invention provides enhancing purity degree of the product.

EFFECT: improved preparing methods of statins.

17 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylated amides of furan and thiophene carboxylic acids of the formulae (Ia) and (Ib) wherein W means oxygen or sulfur atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x means 0, 1, 2 or 3; R(14) means phenyl, and to their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition and using proposed compounds a medicinal agents. Compounds can be used as anti-arrhythmic biologically active substances and especially in treatment and prophylaxis of atrium arrhythmia.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 29 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes valsartan salts chosen from the group involving monosodium, monopotassium, disodium, dipotassium, magnesium, calcium, bis-diethyl (or dipropyl, or dibutyl)-ammonium salts or their hydrates, and mixtures of these salts also. Also, invention relates to a method for their preparing and a pharmaceutical composition comprising thereof. Proposed salts can be in crystalline, partially crystalline, amorphous or polymorphous form. Prepared salts show high quality of crystalline lattices that is a base for chemical and physical stability of new compounds.

EFFECT: improved preparing method, improved and valuable properties of salts.

11 cl, 11 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

FIELD: medicine.

SUBSTANCE: method involves additionally administering vitamins B6, B12 and folic acid to patients receiving anticoagulation therapy. Protein content is limited in daily food allowance to 0.8-1.1 g/kg of body weight and cysteine content is increased to 400-500 mg/day.

EFFECT: enhanced effectiveness of treatment; eliminated homocysteine link in pathogenesis.

FIELD: medicine.

SUBSTANCE: method involves administering Clonidine (Clophelinum). The drug is introduced intramuscularly, intravenously or as pills on the background of neurotropic therapy at a dose of 2.5-3.0 mcg/kg of body weight during the first hours of posttraumatic period within 7-10 days.

EFFECT: accelerated and simplified treatment course.

1 dwg, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used for stabilization of homeostasis and arresting pathological processes in the body. Invention proposes a pharmaceutical composition as powder with particles size from 250 to 400 mcm comprising the following components by the first variant, wt.-%: carbon, 10.01-53.02; oxygen, 30.10-53.10; potassium, 0.26-1.99, and calcium, 0.20-31.37, and comprising the following components by the second variant, wt.-%: calcium, 0.35-31.20; carbon, 10.99-50.21; oxygen, 34.55-51.03; sulfur, 0.73-14.81, and phosphorus, 0.08-3.30. Invention provides compensation of trace elements unbalance that causes and accompanies many diseases, possibility for stabilization of trace element homeostasis and arresting pathological processes of different etiology.

EFFECT: improved and valuable medicinal properties of composition.

12 cl, 13 ex

FIELD: medicine, endocrinology.

SUBSTANCE: invention elates to a method for treatment of diabetes mellitus type 2, method for declining the glucose content in patient blood and method for reducing resistance to insulin, diminishing the hemoglobin A1c content, enhancing the insulin level after eating, and reducing the amplitude change content ("mobility") of glucose in diabetic patients. Method involves administration of metformin to patient in the low dose (160-750 mg) in combination with the second anti-diabetic agent chosen from the group including glucose oxidase inhibitor, glucagons-like peptide-1 (GLP-1), insulin, α/β-double agonist of PRAP other than thiazolidinedione, meglitimide and inhibitor aP2 wherein the second anti-diabetic agent is administrated as a daily dose in interval between the initial daily dose comprising 20-60% of the initial daily dose of this anti-diabetic agent used in usual medicinal practice in therapy of the first order in treatment of diabetes mellitus up to the daily supporting dose comprising 40-60% of the daily supporting dose of this anti-diabetic agent used in usual medicinal practice as therapy of the first order in treatment of diabetes mellitus. Invention provides the effectiveness in treatment of diabetes mellitus that is equivalent practically to effectiveness of treatment by using combination of metformin and other indicated anti-diabetic agent used in doses prescribing in usual medicinal practice but with significantly less adverse effects.

EFFECT: improved method for treatment of diabetes mellitus.

7 cl, 10 dwg, 4 tbl, 3 ex

Up!