EP1124547A1

EP1124547A1 - Pharmaceutical combination of mildronate and enalapril

Info

Publication number: EP1124547A1
Application number: EP99949439A
Authority: EP
Inventors: Ivars Kalvinsh; Maris Veveris; Juris Bundulis; Ilze Skarda
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-10-29
Filing date: 1999-10-27
Publication date: 2001-08-22
Also published as: LV12491A; UA71934C2; EA200100477A1; LV12491B; EA003470B1; WO2000025773A1

Abstract

Pharmaceutical composition, containing 3-(2,2,2-trimethyldrazinium) propionate dihydrate or Mildronate and angiotensin converting enzyme (ACE) inhibitor, as combined preparation for treatment of cardiovascular diseases. It is proposed to use (S)-1-{N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl}-L-proline or Enalapril as ACE inhibitor. The advisable proportion of Mildronate and Enalapryl in the combination is within the range from 8:1 to 12:1.

Description

PHARMACEUTICAL COMBINATION OF MILDRONATE AND ENALAPRIL

This invention is concerned with pharmaceutical compositions in human medicine, viz. pharmaceutical compositions intended for curing of cardiovascular diseases caused by blood circulation disturbances of different origin and localisation, angina pectoris, myocardial infarction, arrhythmias, hypertension, myocarditis, as well as heart failure.

The use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, known also as a medicine Mildronate, Quaterine, THP (GB Patent 2105992) in the treatment of cardiovascular diseases is disclosed. TUP is administered for the treatment of various blood circulation disturbances and ischemic conditions caused by them. However, the influence of THP on, for instance, chronic heart failure is not always sufficient as it eliminates the reduction of the systolic pressure and contractility of the left ventricle only partially, but does not influence the alterations of the diastolic function in case of heart failure appearing as a result of myocardial infarction.

At the same time, a series of ACE inhibitors are known, e.g. (S)-1-{N- [l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl}-L-proline which is known as an antihypertensive drug Enalapril (U.S. Patent 4.374.829) acting as an inhibitor of angiotensin converting enzyme.

Also Enalapril has only a positive influence on the systolic function during the period after myocardial infarction, but has no essential influence on the diastolic function.

The aim of this invention was the development of a pharmaceutical composition, applicable for the cure of a progressive heart failure, for example caused by myocardial infarction. This aim was unexpectedly achieved by the combination in the pharmaceutical composition of Mildronate with an ACE inhibitor, for example, Enalapril.

For such a composition, not only the summarising of the effects, characteristic for both drugs, or the synergistic intensification of these effects, i.e. positive protective influence on the development of myocardial infarction, the disorders of heart rhythm and contractile ability (+dp/dt), but also an extraordinarily intensive influence on the ability of cardiac relaxation (-dp/dt) and an the increase of diastolic pressure in the left ventricle, as well as preservation of the left ventricle size without symptoms of hypertrophy or dilatation were observed. Thus, the claimed pharmaceutical composition allows for a much better and more complete cure of cardiovascular diseases, namely, the cure of chronic heart failure during the period after myocardial infarction, as compared to that observed with each of these drugs in monotherapy. This is an unexpected effect since THP has a low or no influence on blood pressure, therefore it could not be expected that THP would essentially improve the influence of the known antihypertensive drug - Enalapril on the relaxation of cardiac muscle by reducing the end-diastolic pressure and simultaneously increasing the relaxation rate (-dp/dt), what jointly means an extremely positive influence on the diastolic function of myocardium. The suitability of the combination of two known drugs - THP (Mildronate) and the ACE inhibitor, for example, Enalapril for the cure of chronic heart failure and the prevention of the progress of this disease, was verified experimentally. Progressive rat heart failure caused by an experimental myocardial infarction was used as a model which is generally recognised and closely simulates clinical conditions. Myocardial infarction was produced by the ligation of the left coronary artery. The animals with experimental myocardial infarction were treated with each compound of the disclosed combination separately as well as with combination thereof. The significant prevention of the reduction of systolic and diastolic function due to combination of the instant invention was observed. Besides this, the disturbances of the cardiac rhythm did not appear in the group of animals, treated with said combination.

Thus, the pharmaceutical composition containing 3-(2,2,2- trimethylhydrazinium) propionate dihydrate (Mildronate) and an ACE inhibitor, e.g. (S)- 1 - {N-[ 1 -(ethoxycarbony l)-3 -pheny lpropy 1] -L-alany 1 } -L- proline (Enalapril) may be recommended for the cure of cardiovascular diseases, viz. heart failure and myocardial infarction and is more efficient than each ingredient of the pharmaceutical composition, as unlike the Enalapril monotherapy, the Mildronate and Enalapril combination protects not only from the reduction of the cardiac systolic function, but also from that of the diastolic function and the dilatation of the left ventricle and averts the left ventricle hypertrophy more efficiently than Mildronate monotherahy.

A conclusion is suggested that the pharmaceutical composition of Mildronate and Enalapril protects against progressive heart failure and inhibits the development of hemodynamic and morphologic symptoms more efficiently than each of the ingredients separately does.

Mildronate and Enalapril ratio in the composition may be from 5 : 1 to 15: 1 , preferably from 8: 1 to 12: 1.

In cases when the active ingredients are administered parentally by injections or orally as drops, syrup or beverage, the pharmaceutical composition contains 3-(2,2,2-trimethylhydra-zinium) propionate dihydrate and (S)- 1 - {N- [ 1 -(ethoxycarbony l)-3-pheny lpropy l]-L-alanyl } -L-proline in the amount of 0.5-40% by total weight of pharmaceutical form and distilled water, physiologic salt solution, glucose solution, or buffer solution as a pharmaceutically acceptable solvent.

In cases when the active ingredients are administered as tablets, caplets, capsules, pills, granules, or powders, pharmaceutical composition contains 0.01-0.5 g of 3-(2,2,2-trimethyl-hydrazinium) propionate dihydrate and (S)-l-{N-[l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl}-L-proline by weight per tablet, caplet, capsule, pill, granule, or powder dosage unit..

In cases when the active ingredients are administered transcutaneously, their content in the ointment, oil, or plaster is 0.5-40% by total weight of pharmaceutical form.

In case when the active ingredients are administered rectally, their content in the suppository or microclyster is 0.5-40% by total weight of pharmaceutical form.

The following examples, containing the more detailed description of the qualities and application of the proposed composition, are useful for better understanding of the invention.

Examples

Example 1. The experimental treatment of heart failure and myocardial infarction.

The experiments were performed with male rats (310-355 g) of Wistar line. Under pentobarbital anaesthesia (50 mg/kg) in aseptic conditions, the opening of the thorax and that of the cardiac bursa was performed and a loop of twist (sterile Eticon 6/0 thread with an atraumatic needle) was put around the left coronary artery on the level of the left auricula atrii. The quality of manipulation was assessed with a surgical microscope, and the coronary artery of the rat was ligated. Concurrently an ECG was recorded, the wound closure performed and pneumothorax was discontinued. During the operation, in case of need artificial respiration was applied by the use of apparatus V 5kG (Narco Bio-Systems, U.S.A.). Bicillin-1 (500,000 i.u./kg) was administered i.m. for the prophylaxis of postoperative infection. 48 hours after the operation, the animals were weighed, the occurrence and seriousness of infarction was determined and the animals were randomly distributed into 4 groups (the 5th group, that of "sham control", consisted of rats subject to "sham" operation when no ligation of the coronary artery was performed). The mortality during the operation and 48 hours after it equalled on average 29%. Death was mainly caused by ventricular fibrillations. Each group comprised 10 animals (the infarction control group - 12) who were treated as follows (the substances being administered through a stomach probe):

I. Myocardial infarction control (MI) - 2 ml/kg 0.9% NaCI sol. p.o. once daily for 28 days;

II. Myocardial infarction + Mildronate (MI+Mildronate) - 50 mg/kg p.o. once daily for 28 days;

III. Myocardial infarction + Enalapril (MI+Enalapril) - 5 mg/kg p.o. once daily for 28 days;

IV.Myocardial infarction + Mildronate + Enalapril (MI + Mildronate 4-

Enalapril) - 50+5 mg/kg p.o. once daily for 28 days;

V. Sham operated animals (control).

Throughout the treatment course, the general condition of animals was estimated and once a week their body weight was determined. After the treatment schedule (after 4 weeks), the animals were repeatedly weighed and anaesthetised (pentobarbital 50 mg/kg i.p.) and the symptomatology of heart failure was determined: ECG as II standard record, blood pressure from aorta, pressure in the left ventricle (catheterised through a. carotis) and +dp/dt, -dp/dt (with the Polygraphic system RP 6000 Nihon Kohden, Japan) were recorded.

The following parameters were evaluated: average blood pressure, pulse frequency and rhythmicity, the maximal and the minimal pressure of the left ventricle, +dp/dt, -dp/dt; body weight, the mass of heart and that of the left ventricle, the area of infarction wound and the volume of the left ventricle.

After a month from the coronary artery binding, explicit symptoms of heart failure: reduced systolic pressure of the left ventricle, increased end-diastolic pressure and decreased contractility of the left ventricle (Table 1) were observed for uncured animals. For six from nine surviving rats, disorders of cardiac rhythmicity, mainly extrasystoles (Table 2) were observed, but the average blood pressure and pulse frequency did not vary statistically among the groups (Table 1).

The 28 days Mildronate therapy course protects from the reduction of the systolic pressure and that of the contractility of the left ventricle, but the influence on the diastolic pressure is expressed more slightly.

Enalapril administration protects from the reduction of the cardiac systolic function (on grounds of the systolic pressure of the left auricle and +dp/dt), but there is no explicit protection against the reduction of the diastolic pressure (Table 1 ). In case of both drugs combination, also no disorders of cardiac rhythmicity were observed (Table 2).

During the treatment course, weight of all animals increased on the whole similarly, there were no variations in heart mass, too (Table 3 ). However, when the heart mass/body mass ratio is calculated, a heart mass increase is observed in the uncured, as well as in myocardial infarction group cured with Mildronate. On the contrarty, for the animals cured with Enalapril or with Mildronate and Enalapril combination no differences in the weight of heart or its parts from the parameters of the sham operated control group are observed (Table 3).

The macroscopic heart analysis shows that the binding of the coronary artery causes a transmural myocardial infarction in the free anterior wall of the left ventricle. Within a month from the induced infarction, the infarction zone is filled by interstitial tissue and forms a clearly distinguishable scar. The start of the treatment course after 48 hours from the induction of myocardial infarction has no essential influence on the area of the infarction wound (Table 4).

In a 1 month period, the volume of the left ventricle considerably increased for the group of uncured animals as compared with the sham group. It was found to be dilatated and hypertrophied (Table 3 and 4). The experimental results demonstrate that the pharmaceutical composition of Mildronate and Enalapril also essentially protects from the increase of the left ventricle volume (Table 4) this data surprisingly being better than that of the group cured with Enalapril.

During the 28 days therapy course, not a single animal perished from the cured groups and the control one, but 3 from the 12 animals of the myocardial infarction control group did not survive till the end of the experiment (Table 2).

Example 2. The use of composition for the preparing of medicament

The following doses of substances are mixed thoroughly: Mildronate - 180g Enalapril - 20 g Lactose - 150 g Magnesium stearate - 2.0 g

The mixture so prepared is filled into the hard gelatine capsules, thus, the final pharmaceutical form - capsules, each containing 0.2 g of the mixture of active substances, is obtained.

Table 1

Cardie hemodynamic parameters of animals with heart failure caused by mycardial infarction, those cured with Mildronate, Enalapril and both drugs combination in comparison to operated animals without infarction induction (control).

* - p < 0.05 in relation to control ** - p < 0.01 in relation to control

" p < 0.05 in relation to MI

- p < 0.01 in relation to MI

& - p < 0.05 in relation to MI+Mildronate

- p < 0.05 in relation to MI+Enalapril

Table 2

The number of animals surviving the experiment and the analysis of disorders of cardiac rhythm.

+ p < 0.05 in relation to control # p < 0.05 in relation to MI

Table 3

Body weight at experiment beginning and end and heart mass of animals with heart failure caused by myocardial infarction (MI), those cured with Mildronate, Enalapril and both drugs combination in comparison to operated animals without infarction induction (control)

* - p < 0.05 in relation to control

# - p < 0.05 in relation to MI

Table 4

Left ventricle volume and infarction scar area for animals with heart failure caused by myocardial infarction (MI), those cured with Mildronate, Enalapril and both drugs combination in comparison to operated animals without infarction induction (control).

03

- p < 0.05 in relation to control

- p < 0.01 in relation to control

# " p < 0.05 in relation to MI

0 - p < 0.05 in relation to MI+Enalapril

Claims

1. Pharmaceutical composition, containing 3-(2,2,2-trimethyldrazinium) propionate dihydrate or Mildronate and angiotensin converting enzyme (ACE) inhibitor, as combined preparation for treatment of cardiovascular diseases.

2. Pharmaceutical composition, according to Claim 1 , where said ACE inhibitor is (S)- 1 - {N-[ 1 -(ethoxycarbony l)-3-pheny lpropy l]-L-alanyl } -L- proline or Enalapril.

3. Pharmaceutical composition, according to Claim 2, where the proportion of said active substances 3-(2,2,2-trimethyldrazinium) propionate dihydrate and (S)-l-{N-[l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl}-L- proline is within the range from 5: 1 to 15: 1 , advisable from 8: 1 to 12:1.

4. Use of the pharmaceutical composition according to any of the above Claims, for manufacturing of medicament providing for treatment of cardiovascular diseases.