Application of vasopeptidase inhibitor for treating stenocardia

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

 

In the last few years in the patent and technical literature were reported compounds which activity, inhibiting the enzyme that converts angiotensin (ACE), and the activity of inhibiting neutral endopeptidase (EC 11, NEP). These compounds are of interest as cardiovascular agents, especially in the treatment of hypertension, congestive heart failure and kidney disease. These compounds also known as inhibitors of vasopeptidase, dual metalloprotease, NEP/ACE or ACE/NEP. Omapatrilat is an inhibitor vasopeptidase, which is currently the subject of clinical research. Omapatrilat has the chemical name [4S-[4α(R*), 7α, 10αβ]]octahydro-4-[(2-mercapto-1-oxo-3-phenyl-propyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid and the structural formula is:

Omapatrilat, its acquisition and its use for the treatment of cardiovascular diseases described in U.S. patent 5508272.

BMS 189921 is another inhibitor vasopeptidase, which is currently the subject of clinical research. BMS 189921 represents [S-(R*, R*)]hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepin-1-acetic acid structural formula:

BMS 189921, its acquisition and its use in the treatment of cardiovascular diseases described in U.S. patent 5552394.

The invention

This invention is directed to the use of the inhibitor vasopeptidase to treat and/or alleviate symptoms of angina. Preferred for this purpose inhibitors vasopeptidase are omapatrilat or its pharmaceutically acceptable salt, BMS 189921 or its pharmaceutically acceptable salt, or a mixture thereof. Most preferably the use of omapatrilat.

According to the present invention for the treatment of angina, you can apply one or more inhibitors vasopeptidase alone or in combination with each other. The inhibitor or inhibitors vasopeptidase can also be used in combination with one or more pharmaceutically active agents, known for the treatment of angina. Such agents include long-acting nitrates, β-adrenergic blocking agents, blockers penetration of calcium, antithrombin etc. combinational therapy can be used in the preparation of unit doses containing the inhibitor or inhibitors vasopeptidase or their pharmaceutically acceptable salts, and the other agent or agents used to treat angina, joint introduction of individual doses of each active agent or the introduction of a separate doses each the CSOs active agent in accordance with the scheme.

Brief description of figures

Figure 1 presents a graph showing the effect of the inhibitor vasopeptidase of omapatrilat that reflects the sloping line of Frank-Starling's law, after 30 minutes of the development of ischemia on the model of the isolated pehotnogo rat heart.

Figure 2 presents a bar graph showing the effect of the inhibitor of the enzyme that converts selective angiotensin, fosinoprilat reflected on the inclined line of the Frank-Starling on the same model of isolated pehotnogo rat heart.

Detailed description of the invention

Angina is usually described as discomfort in zagrodny region, manifested in the form of compression, or pressure, or a feeling of inflammation. Characteristically, it is not characterized by any specific place, that is, the patient may not show the exact spot where it hurts. Discomfort may be felt in the left shoulder or arm or in the neck and jaw. Some patients describe angina atypical terms as "a sharp pain when flatulence, discomfort only in the region of the jaws, teeth, arms or back or discomfort that starts in the upper abdomen and spreads to the chest area. Some patients describe it as shortness of breath without discomfort, this symptom is called equivalent shortness of breath angina.

Angina occurs when potrebnosti in myocardial oxygen increases to levels which does not meet the increased current coronary blood, usually due to starosnih atherosclerotic lesions in one or more epicardial coronary vessels. Accordingly, angina usually occurs when physical exhaustion or emotional stress. The majority of patients with stable angina may call a special activity or situation, which predictably eliminates discomfort; typical examples are walking on a flat surface or Express walk. It is not unusual to different threshold effort. Activities in cold weather, after a meal or early in the morning is likely to cause angina. Some patients report that efforts are raised above the head with hands cause discomfort. Different threshold efforts leading to the development of angina in some patients, suggest that dynamic changes current coronary blood (for example, due to a sharp increase in coronary vasomotor tone) lead to a fixed atherosclerotic stenosis in limiting blood flow. Episodes of stable angina usually occur gradually and last for 2-10 minutes. Discomfort is usually quickly disappears with rest or sublingual introduction of nitroglycerin.

Stress-induced angina occurs also among some is that patients with valvular stenosis of the aorta, with left ventricular hypertrophy coronary or pulmonary hypertension in the absence of a significant stenosis of the coronary arteries. In these situations, even normal coronary blood flow may be insufficient to meet the needs in the increased number of myocardial oxygen. Angina may also develop in individuals with very dilatrane left ventricles, especially when this is accompanied by reduced diastolic coronary perfusion pressure, as in aortic regurgitation.

Angina that has developed recently or suddenly progressed in severity, frequency or duration of attacks - especially if it is accompanied by residual pain, is considered to be unstable. Patients with recent strokes, especially if they occur at low activity or while resting, also belong to this category. The majority of patients with unstable angina suffer from obstructive coronary disease; unpredictable attack of the disease or the transition from stable to unstable form usually occurs during the formation of cracks in the atherosclerotic plaque with superimposed or platelet-enriched fibrin clot.

Unstable form may be complicated also extracoronary factors (secondary unstable angina). Strong what I anemia or exposure to carbon monoxide, for example, restricts the ability of blood to transfer or release oxygen and can cause angina in terms that the patient with coronary disease usually tolerates. Uncontrolled systemic arterial hypertension, severe arrhythmia, or hypoxemia due to pulmonary disease can also cause the development of angina, and hyperthyroidism. Prinzmetal's angina is similar in nature and the place of occurrence of pain on stable angina and often responds to nitroglycerin. Characteristically, her attacks occur at rest, but without apparent provocation or preceding increase in heart rate or blood pressure. These characteristics are explained by the mechanism of attack: transient spasms of the coronary artery. This often happens early in the morning. Some patients suffering from angina Prinzmetala reported other vasomotor symptoms, such as migraine or phenomenon, Raynaud's disease, see Textbook of lnternel Medicine, Third Edition, pages 316-317 (1997).

This invention is directed to the use of one or more inhibitors vasopeptidase to treat and/or alleviate symptoms of angina. Preferred for this purpose inhibitors vasopeptidase are omapatrilat or its pharmaceutically acceptable salt and BMS 189921 or its pharmaceutically priemel who may salt, especially omapatrilat. The inhibitor vasopeptidase you can enter the patient suffering from angina pectoris, in the amount of from about 0.1 mg/kg to about 2.0 mg/kg over 24 hours, preferably from about 0.3 mg/kg to about 1.0 mg/kg per 24 hours. The inhibitor vasopeptidase can be entered within 24 hours of one or several doses to ensure the total amount of active substance in the above ranges. If within 24 hours you enter more than one dose, the doses can be the same or they may vary. Of course, the amount of applied active substances is regulated by the doctor depending on the type and severity of angina. If used in combination with inhibitors vasopeptidase, one or both of the inhibitor can be introduced in a smaller amount, provided that the total amount is in the above range.

The inhibitor vasopeptidase preferably be administered orally in the form of tablets or capsules. However, you can use other methods of administration, including sublingual, buccal, parenteral, for example, subcutaneous, intravenous or intramuscular injection or infusion method, through the nose, for example, inhalation, local, for example, in the form of creams or ointments, ceremony, for example, in the form of a patch placed on the skin, or rectally, such as suppositories. Various dozirovanno the e drugs in addition to the inhibitor vasopeptidase contain conventional pharmaceutically acceptable carriers, stabilizers, conservatives, lubricating agents, diluents, and other conventional additives. The drug can be used for immediate release or slow release.

Another aspect of the present invention is a method for the treatment of angina one or more inhibitors vasopeptidase, as described above, in combination with another class of pharmaceutically active substances used in the treatment of angina. Such substances include long-acting nitrates, such as nitroglycerin, isosorbide Mononitrate, isosorbide dinitrate treatment, β-adrenergic blockers, e.g., hydrochloride propranolol, maleate timolol, carvedilol, tartrate and atenolol and antagonists of a calcium intake, such as amlodipine besylate, diltiazemcream and verapamilverapamil. The present invention also relates to the combination of one or more inhibitors vasopeptidase and pharmaceutically active substances used to treat angina, such as antithrombin. Such antithrombin include clopidogrel, ticlopidine, aspirin and dipyridamole. When such combined therapy is usually used such a number of long-acting nitrate, β-adrenergic blocker, blocker receipt of calcium and/or anti-thrombin, which is already recommended for the treatment of angina ilizhe doctor is assigned to a smaller number. Similarly, when combination therapy number of inhibitor vasopeptidase may be less than specified above when alone. The inhibitor vasopeptidase and the other pharmaceutically active agent or agents can be used in a single dosage form, or administered together as separate dosage forms, or applied separately in accordance with the assigned schema.

The term "pharmaceutically acceptable salt" includes salts of alkali metals, e.g. sodium and potassium, salts of alkaline earth metals such as calcium and magnesium, salts of amino acids such as arginine, lysine, etc. and salts of amines, such as alkylamines followed, for example, trebutien, tretamine etc., substituted alkylamines followed, for example, benzylamine, dialkylamino, substituted dialkylamino, for example, N-methylglucamine, dialkylamino, substituted dialkylamino, and Quaternary ammonium salt. The following examples illustrate the activity of the inhibitor vasopeptidase of omapatrilat against angina.

Example 1.

The model of isolated pehotnogo rat heart affected by ischemia.

Method.

The male rats Sprague-Dawley (350-450 g) eve were not given any food and then anestesiologi their pentobarbital sodium (30-40 mg/kg, intraperitoneally). Performed the intubation by dissection of the trachea, then the artificial ventilation of the animal the x was made using the respirator (Model 683, Harvard Instruments, South Natick, MA) with tidal otlivnyy volume of 4-5 ml, dostavljenim speeds of 65-75 breath/min and was held anticoagulation with heparin sodium (1000 m IU/kg) via the external jugular vein. Was performed by thoracotomy and retraction of the ribs and exposed heart. The pericardium was removed and cleaned the ascending part of the aorta from the connective tissue. Around the base of the aorta to secure the cannula to the perfusion was placed 2-0 silk thread. Then pinched the inferior Vena cava and made an incision at the base of the aorta. The incision was quickly inserted a steel cannula connected with shutoff valve and secured it with a thread. Conducted in vitro retrograde perfusion oxygendemand (95% oxygen, 5% carbon dioxide, pH 7.4) solution of Krebs-Henseleit containing (in mm) 1.25 calcium chloride, 112 of sodium chloride, 25 sodium bicarbonate, 5 KCl, 1 diphosphate potassium, 1.2 magnesium sulfate and 5.5 dextrose. Then the heart was placed in a standard Langendorff apparatus for perfusion (Doring et aL, The isolated perfused warmblooded heard according to Langendorff, 1sted. March: Biomesstechnik-Verlag; 1988), where he implemented the perfusion oxygendemanding buffer Krebs-Henseleit, negratin to 37°With, at constant pressure perfusion, equal to 86 mm RT. senior water Filled balloon made of latex was removed from the holder (#55613-413, VWR Scientific, S. Plainfield, NJ) was attached to the cannula stainless steel (model LL2, Hugo Sachs, March-Hugstetten, Germany), cat is the ROI was then placed in the left ventricle. The cannula was attached to a pressure transducer (model R23 is applied, Gould Instruments, Valley View, OH) to measure arising in the ventricle efforts. Then the heart was placed in a bath with water-jacketed (37°). Current perfusion solution was controlled using extracorporeal electromagnetic probe (model MDL 1401, Skalar Instruments, Litchfield, CT). Hearts beat with normal frequency. All data are continuously presented in a digital form at a frequency of 250 Hz for further analysis (Po-Neh-Mah Acquisition System, Gould Instruments, Valley View, OH). Based on the obtained digital data received sustainable values of heart rate, current perfusion solution and developed left ventricular pressure (LV systolic pressure, LV end-diastolic pressure) during the study, the preliminary injection of medications, a reduced flow rate. Hearts were prepared and investigated in quadriplicate.

The work of the ventricle.

Periodic independent indexes of work of the myocardium was obtained as the average value of the slope of the linear part of the triplet curves Frank-Starling (FS) [Schlant, Normal discrimination of the cardiovascular system. In: Hurst JW, ed. The Heart, 4thed. New York: McGraw-Hill; 1978: 71-100]. Also recorded and averaged, the average peak pressure developed in the left ventricle (LVDPmaxreceived during each discrete series of curves FS. Curves FS was obtained by nadalia tank, located in the ventricle with a constant is korostil 50 μl/min using a pump with programmable cycle bloating/descent (model 44, Harvard Apparatus, South Natick, MA). Natalie cylinder was interrupted at the time of the slope of the curve segment FS defined at the point where the pressure developed in the left ventricle (LVDP), decreased with a further increase of the volume of the container (pre-load). Then the volume of the cylinder is reduced at the rate of 300 µl/min up until LVDP does not cease to be measured (<2 mm Hg). This process was repeated to obtain three reproducible curves.

Preparation of a medicine and the introduction of it.

Compound was dissolved in dimethyl sulfoxide (DMSO) in the amount of h concentration delivered to the body, and then poured the solution into the distal perfusion flow of each heart using a programmable pump (model 22, Harvard Apparatus, South Natick, MA). Each pump was controlled by a computer program, which continuously recorded the perfusion flow in every heart and dynamically adjust the rate of infusion of the test compound to maintain the concentration of DMSO equal to 0,04%. Control hearts were treated similarly, but without the drugs.

The Protocol of the experiments.

With this model, an inhibitor vasopeptidase omapatrilat compared with the carrier and selektivnym inhibitor of the enzyme that converts angiotensin, fosinoprilat (fosinopril in the form of the free acid). Omapatrilat was introduced in 20 hearts, wear the spruce - 21 and fosinoprilat - 19.

The maximum dose of each compound was limited to a maximum hemodynamic dose, without giving effect attainable for normal hearts, in order to avoid unwanted effects of cardiodepressive caused by drugs that affect the ventricles.

After 5 min equilibrium period, the control FS curves were obtained for each heart and also recorded for each heart LVDPmax. Then regulate experimental preload (volume of cylinder) to the size of a single volume of the container, providing 70% LVDPmaxin every heart. This volume was supported, as described in detail below. Then, as soon as the specified pre-load was achieved in all hearts, was followed by a 5 - min control period. At this moment began the infusion or medication, or media and continued it until the end of the experience.

In order to avoid unwanted inotropic actions of medications, dispensing medications during ischemia with low shock was supposed to end when the greatest amount of concentration that does not affect stable hemodynamics under normal pressure perfusion.

After a 5 - min control period was injected a drug at a constant infusion for 10 minutes at normal perfusion (86 mm Hg) and in accordance with what their 45 minutes of ischemia with low flow (50 mm Hg). The ratio of the slope of the curves of the Frank-Starling (FS) was used as an independent index reduction function of the ventricle during the control period and ischemia with low flow. All FS data were normalized and expressed as a percentage of control values FS for each heart. Group data for all such groups and expressed them as mean ±sem (standard deviation of the mean). All group data were compared by the method of variance analysis. The value of p<0,05 was considered significant (table 1).

Table 1

Omapatrilat
Dose (μm)031030
% from the reference value of the tilt FS48,157,063,571,1
sem2,74,23,3a 3.9
Fosinoprilat
Dose (μm)01030
% from the reference value of the tilt FS47,749,452,3
sem 2,73,43,4
 

A graphical representation of these data is shown in figure 1 (omapatrilat) and Figure 2 (fosinoprilat).

These data show that the inhibitor vasopeptidase omapatrilat changed the slope of the FS, depending on the dose (R2=0,99), while selective inhibitor that converts angiotensin, fosinoprilat, slightly differed from the media at equimolar doses.

Example 2.

Model dog with dysfunction of effort.

Omapatrilat (0.3 mg/kg intravenously, n=7) were evaluated on the model of the dog with myocardial dysfunction efforts (Matsuzaki et al., "Effects of a calcium entry blocker (diltiazem) on regional myocardial flow and function during exercise in conscious dogs", Circulation, 1984, 69, 801-814). Dogs, equipped with a technical device, driven muscle strength with perfusion collateral dependent rear wall, were trained to run on topcase supplied with the engine. At the end of the control period (stage-2) and drug administration (stage-1) started exercise (stage-1) and increased it every two minutes, up until the heart rate will not cease to increase with increase in load or stop it. The maximum load was set at Stage 7. Recovery phase (8, 9) after exercise also lasted for two minutes. Was observed following achiev Italy (table 2).

Table 2

Stage exercisesSpeed (m/h)KcalRate Topeka (C)
-200,80
-100,80
000,80
12,52,20
23,42,80
33,44,65
43,46,410
53,48,215
63,410,020
73,411,825
83,42,80
92,52,20
 

Continuously measured systemic hemodynamics, local thickening of the wall of the myocardium and filmed local electrogram ventricles, these data are translated into digital form for further analysis. All exercises were performed on pairs of dogs, the introduction of the medium was accompanied by the ü 4 hours introduction omapatrilat. All data were normalized and expressed as a percentage of the corresponding control value. All groups were compared by analyzing the variance or using a t-test. The data obtained, as known and published in the form of such protocols, show that a full recovery after a single exercise with a large load occurs within 3 hours. In the above study, a full recovery after a quiz is confirmed by the fact that all hemodynamic values before the second (omapatrilat) exercise was recovered 100% from the control (media).

In this experience (omapatrilat) (0.3 mg/kg, IV) did not affect significantly the systolic pressure in the left ventricle or on the product: heart rate × systolic pressure in the left ventricle during the control experiment or exercise. Because each dog was observed own point of graduation exercises, all data were expressed as % of control values (with media).

The following data were obtained (table 3-5).

Table 3
Systolic pressure in the left ventricle (LVS)
Stage exercisesMediasem (mean standard error value) Omapatrilatsem
-2129,55.8130,25,6
-1to 129.24,8124,96,3
0128,15,9124,38,1
1142,75,6134,87,2
2of 142.86,6139,26,9
3141,27,3138,96,9
4141,47,8138, 7mm7,0
5of 142.88,2140,36,2
6137,15,9br143.36,4
7to 140.56,4147,57,1
8135,17,9130,56,2
9130,47,8127,45,1

Table 4
Heart rate
Stage exercisesMediasem Omapatrilatsem
-2110,28,6117,38,5
-1106,67,0127,17,8
0117,710,5151,512,3
1168,57,3182,48,1
2185,2the 5.7196,27,7
3192,7of 5.4the amount of 203.97,1
4204,2a 4.9217,16,0
5221,23,4230,76,5
6236,15,3239,46,7
7247,35,9to 245.66,0
8198,34,4206,28,4
9of 174.56,0182,6a 4.9

Based on the above data we can conclude that improvements in the ability to exercise cannot be attributed to changes in the load on the ventricle or in the rate of heartbeat.

X is even though omapatrilat had no effect on systemic hemodynamics, the peak value of the ability to exercise increased in six of the seven dogs that show the following data.

Table 6
The peak value of the ability to exercise (Kcal)
DogMediaOmapatrilat
And11,812,5
In11,812,5
6,48,2
D10,012,5
E8,212,5
F11,811,8
G8,210,0
Averagethe 9.711,4

This increase was accompanied by a significant thickening of the coronary artery wall (p<0.001) and a trend towards reduction increase ST on the corresponding electrogram (p=0.06). The following data were obtained (table 6, 7).

Table 8
The ST segment
Stage exercisesMediasemOmapatrilatsem
-2100,00,0101,42,5
-1102,29,3103,0the 15.6
094,14,6124,519,0
1247,188,2238,350,9
2305,1125,6315,189,8
3336,4128,7308,885,5
4385,9135,6RUR 322.7for 95.2
5401,7122,8348,399,5
6555,6110,2374,1117,0
7  438,3of 101.5
8301,042,6242,759,7
9270,634,0161,923,0

Subsequent thickening of the wall decreased significantly with the introduction of omapatrilat. A corresponding increase in ST segment reflects the function of the ischemic zone. This improves the function corresponds to the improved ability to exercise, shown above.

1 a Method of treating and/or alleviating symptoms of angina, includes introduction to the patient an effective amount of omapatrilat or its pharmaceutically acceptable salt.

2. A method of treating and/or alleviating symptoms of angina, including the introduction of an effective amount of omapatrilat or its pharmaceutically acceptable salt in combination with another pharmaceutically active agent.

3. The method according to claim 2, wherein the other pharmaceutically active agent is administered together with omapatrilat or its pharmaceutically acceptable salt.

4. The method according to claim 2, wherein the other pharmaceutically active agent is administered separately from omapatrilat or its pharmaceutically acceptable salt.

5. The method according to claim 2, wherein the other pharmaceutically active ingredient is an organic nitrate, β-adrenergic blocker, blocker entry of calcium or antiplatelet agent.

6. The method according to claim 5, characterized in that the organic nitrate selected from the group consisting of nitroglycerin, Mononitrate isosorbide and isosorbide dinitrate.

7. The method according to claim 5, characterized in that β-adrenergic blocker selected from the group consisting of hydrochloride propranolol, timelimit, carvedilola, metoprololonline and atenolol.

8. The method according to claim 5, characterized in that the blocker entry of calcium selected from the group consisting of of amlodipine besylate, dilti the earth hydrochloride and verapamil hydrochloride.

9. The method according to claim 5, wherein the antiplatelet agent selected from the group consisting of clopidogrel, ticlopidine, aspirin and dipyridamole.

10. The use of omapatrilat or its pharmaceutically acceptable salts for the preparation of medicaments for treatment and/or relief of symptoms of angina.

11. The use of claim 10 together with another pharmaceutically active agent.

12. The application of claim 11, wherein the other pharmaceutically active agent is an organic nitrate, β-adrenergic blocker, blocker entry of calcium or antiplatelet agent.

13. The application of item 12, wherein the organic nitrate selected from the group consisting of nitroglycerin, Mononitrate isosorbide and isosorbide dinitrate.

14. The application indicated in paragraph 12, in which β-adrenergic blocker selected from the group consisting of hydrochloride propranolol, timolol maleate, carvedilola, metoprolol tartrate and atenolol.

15. The application indicated in paragraph 12, in which the blocker entry of calcium selected from the group consisting of of amlodipine besylate, diltiazem hydrochloride and verapamil hydrochloride.

16. The application indicated in paragraph 12, in which antiplatelet agent selected from the group consisting of clopidogrel, ticlopidine, aspirin and dipyridamole.



 

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where R1-R5, G1-G3and W have the meanings indicated in the claims, and the invention relates to a method for producing these compounds, medicinal product and the method of its production

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

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