EP1124547A1 - Pharmaceutical combination of mildronate and enalapril - Google Patents
Pharmaceutical combination of mildronate and enalaprilInfo
- Publication number
- EP1124547A1 EP1124547A1 EP99949439A EP99949439A EP1124547A1 EP 1124547 A1 EP1124547 A1 EP 1124547A1 EP 99949439 A EP99949439 A EP 99949439A EP 99949439 A EP99949439 A EP 99949439A EP 1124547 A1 EP1124547 A1 EP 1124547A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- enalapril
- mildronate
- pharmaceutical composition
- animals
- myocardial infarction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- 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.
- TUP 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.
- 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.
- ACE inhibitors 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.
- 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.
- 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.
- THP has a low or no influence on blood pressure
- 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 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.
- 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.
- Mildronate and Enalapril ratio in the composition may be from 5 : 1 to 15: 1 , preferably from 8: 1 to 12: 1.
- 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.
- 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.
- 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):
- MI Myocardial infarction control
- Enalapril 50+5 mg/kg p.o. once daily for 28 days;
- ECG ECG as II standard record
- blood pressure from aorta blood pressure in the left ventricle (catheterised through a. carotis)
- +dp/dt, -dp/dt with the Polygraphic system RP 6000 Nihon Kohden, Japan
- 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).
- 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).
- Example 2 The use of composition for the preparing of medicament
- 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.
- MI myocardial infarction
- MI myocardial infarction
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LV980252 | 1998-10-29 | ||
LVP-98-252A LV12491B (en) | 1998-10-29 | 1998-10-29 | Pharmaceutical composition |
PCT/LV1999/000005 WO2000025773A1 (en) | 1998-10-29 | 1999-10-27 | Pharmaceutical combination of mildronate and enalapril |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1124547A1 true EP1124547A1 (en) | 2001-08-22 |
Family
ID=19736545
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99949439A Withdrawn EP1124547A1 (en) | 1998-10-29 | 1999-10-27 | Pharmaceutical combination of mildronate and enalapril |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1124547A1 (en) |
EA (1) | EA003470B1 (en) |
LV (1) | LV12491B (en) |
UA (1) | UA71934C2 (en) |
WO (1) | WO2000025773A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
LV13450B (en) * | 2004-08-24 | 2006-11-20 | Grindeks As | Novel medicinal use of meldonium and pharmaceutical compositions thereof |
EP2420224A1 (en) * | 2010-08-11 | 2012-02-22 | Grindeks, a joint stock company | Method for producing a stable 3-(2,2,2-trimethylhydrazinium)propionate dihydrate solid pharmaceutical composition |
RU2467748C1 (en) * | 2011-08-08 | 2012-11-27 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" | 3-(2,2,2-trimethylhydrazinium) propionate derivative - 3-(2,2,2-trimethylhydrazinium) potassium propionate glycinate exhibiting endothelioprotective activity |
CN105853349A (en) * | 2016-04-29 | 2016-08-17 | 济南康和医药科技有限公司 | Mildronate injection and preparation method thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1254314B (en) * | 1992-03-27 | 1995-09-14 | Sigma Tau Ind Farmaceuti | PHARMACEUTICAL COMPOSITIONS CONTAINING L-CARNITINE AND ACYL-CARNITINE ASSOCIATION WITH ACE-INHIBITORS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES. |
LV11728B (en) * | 1995-08-21 | 1997-08-20 | Kalvins Ivars | Pharmaceutical composition |
-
1998
- 1998-10-29 LV LVP-98-252A patent/LV12491B/en unknown
-
1999
- 1999-10-27 EP EP99949439A patent/EP1124547A1/en not_active Withdrawn
- 1999-10-27 UA UA2001053571A patent/UA71934C2/en unknown
- 1999-10-27 EA EA200100477A patent/EA003470B1/en not_active IP Right Cessation
- 1999-10-27 WO PCT/LV1999/000005 patent/WO2000025773A1/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO0025773A1 * |
Also Published As
Publication number | Publication date |
---|---|
LV12491A (en) | 2000-06-20 |
UA71934C2 (en) | 2005-01-17 |
EA200100477A1 (en) | 2001-10-22 |
LV12491B (en) | 2000-12-20 |
EA003470B1 (en) | 2003-06-26 |
WO2000025773A1 (en) | 2000-05-11 |
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Legal Events
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