WO2009071585A1 - Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate - Google Patents

Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate Download PDF

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Publication number
WO2009071585A1
WO2009071585A1 PCT/EP2008/066711 EP2008066711W WO2009071585A1 WO 2009071585 A1 WO2009071585 A1 WO 2009071585A1 EP 2008066711 W EP2008066711 W EP 2008066711W WO 2009071585 A1 WO2009071585 A1 WO 2009071585A1
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Prior art keywords
meldonium
trimethylhydrazinium
dihydrogen phosphate
hydrogen fumarate
atherosclerosis
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French (fr)
Inventor
Ilmars Stonans
Eduard Tararak
Elena Andreyeva
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CHEMCO VENTURES (CYPRUS) Ltd
Grindeks JSC
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CHEMCO VENTURES (CYPRUS) Ltd
Grindeks JSC
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Priority to DK08857026.2T priority Critical patent/DK2222293T3/en
Priority to MX2010006255A priority patent/MX2010006255A/en
Priority to JP2010536438A priority patent/JP2011505408A/en
Priority to HR20110744T priority patent/HRP20110744T1/en
Priority to CN2008801194045A priority patent/CN101951898B/en
Priority to US12/734,779 priority patent/US20100234459A1/en
Priority to PL08857026T priority patent/PL2222293T3/en
Priority to EA201000738A priority patent/EA019424B1/en
Priority to AU2008333262A priority patent/AU2008333262A1/en
Priority to BRPI0819057 priority patent/BRPI0819057A2/en
Priority to SI200830410T priority patent/SI2222293T1/en
Priority to EP08857026A priority patent/EP2222293B1/en
Application filed by CHEMCO VENTURES (CYPRUS) Ltd, Grindeks JSC filed Critical CHEMCO VENTURES (CYPRUS) Ltd
Priority to CA2706354A priority patent/CA2706354C/en
Priority to AT08857026T priority patent/ATE518536T1/en
Publication of WO2009071585A1 publication Critical patent/WO2009071585A1/en
Priority to ZA2010/03641A priority patent/ZA201003641B/en
Priority to IL205961A priority patent/IL205961A0/en
Priority to TN2010000250A priority patent/TN2010000250A1/en
Anticipated expiration legal-status Critical
Priority to MA32978A priority patent/MA31993B1/en
Ceased legal-status Critical Current

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of 3-(2,2,2-trimethylhydrazinium) propionate salts for the manufacture of a medicament for prevention and therapy of atherosclerosis.
  • Atherosclerosis is a disease affecting arterial blood vessels. It is a chronic inflammatory response in the walls of arteries, in large part due to the deposition of lipoproteins (plasma proteins that carry cholesterol and triglycerides). It is commonly referred to as a "hardening” or “furring” of the arteries. It is caused by the formation of multiple plaques within the arteries.
  • Atherosclerosis is a slow, complex disease that typically starts in childhood and often progresses with age. In some people it progresses rapidly, even in their third decade. The disease is thought to start from damage to the innermost layer of the artery which is called the endothelium. The damage to the arterial wall is caused by: elevated levels of cholesterol and triglyceride (tri-GLIS'er-id) in the blood high blood pressure • tobacco smoke diabetes
  • Atherosclerosis is a great social and medical-sociologic problem and its clinical manifestations are the major contributor to high hospitalisation and death rates.
  • 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is known under International Nonproprietary Name-Meldonium dihydrate.
  • Carnitine and Meldonium are structurally very similar.
  • Carnitine has been used as an anti-atherosclerosis agent, alone or in combination with other drugs, preferably naturally occurring preparates, such as flavonoids or omega-3 series polyunsaturated acids, etc.
  • Patent EP1128822 (SIGMA TAU HEALTHSCIENCE SPA, published in 05.09.2001) discloses a pharmaceutical composition comprising L-carnitine and a flavonoid against thrombosis and atherosclerosis.
  • the aim of the present invention is to get a pharmaceutical substance which is more effective substance than Meldonium dihydrate in prevention and therapy of atherosclerosis.
  • the rabbits were fed with standard diet with 1 % cholesterol dissolved in the sunflower seed oil (4% from the total amount of food).
  • the diet was enriched with cholesterol as follows: 10 kg standard food for rabbits was heated to 60°C and was mixed with 100 g warm cholesterol dissolved in 400 ml sunflower seed oil. The rabbits received 200 g of this food per day.
  • the experimental groups were given Meldonium dihydrate, Meldonium dihydrogen phosphate and Meldonium hydrogen fumarate, in a dose 124 mg/kg, 165 mg/kg and 174 mg/kg.
  • the preparations were added to drinking water. After 15 weeks the rabbits were sacrificed.
  • Heart, aorta and liver were collected for examination. The aorta was stripped of adventitia, cut longitudinally and washed with phosphate buffer solution.
  • Specimens from abdominal, descending and ascending aorta were studied by light microscopy and immunomorphologically. Pieces of aorta were fixed in 4% neutral formaldehyde buffer for 7 days.
  • the aorta, heart and liver were frozen in liquid nitrogen and stored at 70°C. Specimens were fixed in methacarn for preparation of paraffin sections.
  • Table 1 shows that Meldonium dihydrogen phosphate in pharmacological reduces >2-fold the area of atherosclerotic plaque in rabbit aorta compared with control and Meldonium dihydrate groups.
  • Table 2 shows that Meconium's hydrogen fumarate in pharmacological doses reduce >2-fold the area of atherosclerotic plaque in rabbit aorta compared with the control and Meldonium dihydrate groups

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Novel medical use of 3-(2,2,2-trimethylhydraziniunn) propionate salts for the manufacture of a medicament for prevention and therapy of atherosclerosis.

Description

MEDICAL USE OF 3-(2,2,2-TRIMETHYLHYDRAZINIUM) PROPIONATE HYDROGEN FUMARATE AND DIHYDROGEN PHOSPHATE
Technical Field
The present invention relates to the use of 3-(2,2,2-trimethylhydrazinium) propionate salts for the manufacture of a medicament for prevention and therapy of atherosclerosis. Background Art
Atherosclerosis is a disease affecting arterial blood vessels. It is a chronic inflammatory response in the walls of arteries, in large part due to the deposition of lipoproteins (plasma proteins that carry cholesterol and triglycerides). It is commonly referred to as a "hardening" or "furring" of the arteries. It is caused by the formation of multiple plaques within the arteries.
Atherosclerosis is a slow, complex disease that typically starts in childhood and often progresses with age. In some people it progresses rapidly, even in their third decade. The disease is thought to start from damage to the innermost layer of the artery which is called the endothelium. The damage to the arterial wall is caused by: elevated levels of cholesterol and triglyceride (tri-GLIS'er-id) in the blood high blood pressure • tobacco smoke diabetes
See, http://www.americanheart.org/presenter.jhtml7identifier~444Q 04.12.2007 Atherosclerosis is a great social and medical-sociologic problem and its clinical manifestations are the major contributor to high hospitalisation and death rates. 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is known under International Nonproprietary Name-Meldonium dihydrate. Carnitine and Meldonium are structurally very similar.
Carnitine has been used as an anti-atherosclerosis agent, alone or in combination with other drugs, preferably naturally occurring preparates, such as flavonoids or omega-3 series polyunsaturated acids, etc.
Patent EP1128822 (SIGMA TAU HEALTHSCIENCE SPA, published in 05.09.2001) discloses a pharmaceutical composition comprising L-carnitine and a flavonoid against thrombosis and atherosclerosis.
However, the pharmacological effect of Meldonium dihydrate has been regarded as counteracting the effect of carnitine. Meldonium dihydrate has been used in anti-atherosclerosis therapy. Meldonium dihydrate displays hypolipodemic activity in rats with triton WR-1339 hyperlipidemia. (OKUNEVICH IV, RYZHENKOV VE et al, "Anti-atherosclerotic action of Meldonium dihydrate in experiment", published in "Patologiteskaja
Fiziologija I Experimentaljnaja Terapija" 2002, Apr-Jun vol.2, p.24-7). An experiment that describes atherosclerosis in coronary, cerebral and peripheral blood-vessels shows that Meldonium dihydrate exerts a beneficial effect on the regional circulation, lipid metabolism and can be used in the treatment of patients with concomitant forms of atherosclerosis (see KARPOV RS, DUDKO VA. "The clinical instrumental evaluation of treatment efficacy in patients with concomitant atherosclerosis of the coronary, cerebral and peripheral arteries", published in
"Terapevticheskii Arkhiv" 1991. vol.63, no.4, p.90-93).
Dihydrogen phosphate and hydrogen fumarate salts of Meldonium are disclosed in EP 1667960 A (JOINT STOCK COMPANY GRINDEKS) 14.06.2006 as more stable substance comparatively with Meldonium dihydrate. Disclosure of Invention
Technical problem
Irrespective of a vast range of pharmacological preparations used to treat patients with atherosclerosis, the disease if not dully controlled.
The aim of the present invention is to get a pharmaceutical substance which is more effective substance than Meldonium dihydrate in prevention and therapy of atherosclerosis.
We unexpectedly have found that salts of Meldonium - Meldonium dihydrogen phosphate and Meldonium hydrogen fumarate, effectively reduce atherosclerotic manifestations in the aorta. Anti-Atherosclerotic experiment
Pharmacological experiment was carried out to examine the anti-atherosclerotic effect of Meldonium dihydrogen phosphate or Meldonium hydrogen fumarate in the aorta.
The experiments with Meldonium salt such as Meldonium dihydrogen phosphate or Meldonium hydrogen fumarate, were performed in 38 Chinchilla rabbits weighing 2.5-3.0 kg. The rabbits were randomly divided into 4 groups: Control (n=11), Meldonium dihydrate group (n=9) and Meldonium dihydrogen phosphate group (n=9) and Meldonium hydrogen fumarate group (n=9). Experimental atherosclerosis, i.e. serum hyperlipidaemia and the atherosclerotic manifestations in the aorta, was induced by administering 1 % cholesterol by weight together with standard diet.
The rabbits were fed with standard diet with 1 % cholesterol dissolved in the sunflower seed oil (4% from the total amount of food). The diet was enriched with cholesterol as follows: 10 kg standard food for rabbits was heated to 60°C and was mixed with 100 g warm cholesterol dissolved in 400 ml sunflower seed oil. The rabbits received 200 g of this food per day.
The experimental groups were given Meldonium dihydrate, Meldonium dihydrogen phosphate and Meldonium hydrogen fumarate, in a dose 124 mg/kg, 165 mg/kg and 174 mg/kg. The preparations were added to drinking water. After 15 weeks the rabbits were sacrificed. Heart, aorta and liver were collected for examination. The aorta was stripped of adventitia, cut longitudinally and washed with phosphate buffer solution. Specimens from abdominal, descending and ascending aorta were studied by light microscopy and immunomorphologically. Pieces of aorta were fixed in 4% neutral formaldehyde buffer for 7 days. For further investigations the aorta, heart and liver were frozen in liquid nitrogen and stored at 70°C. Specimens were fixed in methacarn for preparation of paraffin sections.
After fixation in formaldehyde the specimens were washed for 24 hours in running water, stained with Oil red O by the standard method and examined for the presence of lipid spots, streaks and plaques. In all rabbits atherosclerotic changes were observed in the total preparations of the aorta stained with Oil red O. Results of these tests show that and Meldonium dihydrogen phosphate is capable of reducing the spots of atherosclerosis manifestations, see Table 1. Anti-Atherosclerotic activity of Meldonium dihydrogen phosphate
Figure imgf000005_0002
Figure imgf000005_0001
Table 1 Effect of Meldonium dihydrogen phosphate on atherosclerotic manifestations in rabbit aorta.
*p<0.05 compared with the control group; #p<0.05 compared with Meldonium dihydrate group.
Table 1 shows that Meldonium dihydrogen phosphate in pharmacological reduces >2-fold the area of atherosclerotic plaque in rabbit aorta compared with control and Meldonium dihydrate groups.
The results of these tests show that Meldonium's hydrogen fumarate reduces atherosclerosis manifestations see Table 2. Anti-A aretherosclerotic activity of Meldonium hydrogen fumarate
Figure imgf000006_0002
Figure imgf000006_0001
Table 2 Effect of Meldonium hydrogen fumarate on atherosclerotic manifestations in rabbit aorta.
*p<0.05 compared with control group; #p<0.05 compared with Meldonium dihydrate group
Table 2 shows that Meconium's hydrogen fumarate in pharmacological doses reduce >2-fold the area of atherosclerotic plaque in rabbit aorta compared with the control and Meldonium dihydrate groups

Claims

Claims
1. Use of 3-(2,2,2-trimethylhydrazinium) propionate salt selected from the group consisting of dihydrogen phosphate and hydrogen fumarate for manufacture of a medicament for prophylaxis and/or treatment of atherosclerosis. 2. A salt of 3-(2,2,
2-trimethylhydrazinium) propionate for prophylaxis and/or treatment of atherosclerosis.
3. 3-(2,2,2-Trimethylhydrazinium) propionate salt according to claim 1 or claim 2 where it is 3-(2,2,2-trimethylhydrazinium) propionate dihydrogen phosphate.
4. 3-(2,2,2-Trimethylhydrazinium) propionate salt according to claim 1 or claim 2 where it is 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate.
PCT/EP2008/066711 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate Ceased WO2009071585A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
AT08857026T ATE518536T1 (en) 2007-12-04 2008-12-03 MEDICAL USE OF 3-(2,2,2-TRIMETHYLHYDRAZINIUM) PROPIONATHYDROGENE FUMARATE AND DIHYDROGEN PHOSPHATE
SI200830410T SI2222293T1 (en) 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
JP2010536438A JP2011505408A (en) 2007-12-04 2008-12-03 Method for using hydrogen fumarate and dihydrogen phosphate of 3- (2,2,2-trimethylhydrazinium) propionate in medicine
HR20110744T HRP20110744T1 (en) 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
CN2008801194045A CN101951898B (en) 2007-12-04 2008-12-03 Medical uses of 3-(2,2,2-trimethylhydrazine) propionate hydrofumarate and dihydrogen phosphate
US12/734,779 US20100234459A1 (en) 2007-12-04 2008-12-03 Medicall use of 3-(2,2,2,-trimethylyhdrazinium) propionate hdrogen fumarate and dihydrogen phosephate
PL08857026T PL2222293T3 (en) 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
EA201000738A EA019424B1 (en) 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium)propionate hydrogen fumarate and dihydrogen phosphate
AU2008333262A AU2008333262A1 (en) 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
DK08857026.2T DK2222293T3 (en) 2007-12-04 2008-12-03 Medical use of 3- (2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
EP08857026A EP2222293B1 (en) 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
MX2010006255A MX2010006255A (en) 2007-12-04 2008-12-03 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate.
BRPI0819057 BRPI0819057A2 (en) 2007-12-04 2008-12-03 "USE OF 3- (2,2,2-TRIMETHYLHYDRAZINE) PROPIONATE AND ITS SALTS"
CA2706354A CA2706354C (en) 2007-12-04 2008-12-03 Use of hydrogen fumarate and dihydrogen phosphate salts of meldonium in treating or preventing atherosclerosis
ZA2010/03641A ZA201003641B (en) 2007-12-04 2010-05-21 Medical use of 3-(2,2,2-trimethylhydrazinuim) propionate hydrogen fumarate and dihydrogen phosphate
IL205961A IL205961A0 (en) 2007-12-04 2010-05-25 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
TN2010000250A TN2010000250A1 (en) 2007-12-04 2010-06-01 Medical use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate and dihydrogen phosphate
MA32978A MA31993B1 (en) 2007-12-04 2010-07-01 New medical use of 3-salts (2,2,2-trimetylhydrazinium) propionate

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07122273.1 2007-12-04
EP07122273 2007-12-04
EP07122272.3 2007-12-04
EP07122272 2007-12-04

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US (1) US20100234459A1 (en)
EP (1) EP2222293B1 (en)
JP (1) JP2011505408A (en)
KR (1) KR20100084688A (en)
CN (1) CN101951898B (en)
AR (1) AR069521A1 (en)
AT (1) ATE518536T1 (en)
AU (1) AU2008333262A1 (en)
BR (1) BRPI0819057A2 (en)
CA (1) CA2706354C (en)
CL (1) CL2008003551A1 (en)
CO (1) CO6280477A2 (en)
CY (1) CY1112336T1 (en)
DK (1) DK2222293T3 (en)
DO (1) DOP2010000163A (en)
EA (1) EA019424B1 (en)
GE (1) GEP20125673B (en)
HR (1) HRP20110744T1 (en)
IL (1) IL205961A0 (en)
MA (1) MA31993B1 (en)
MX (1) MX2010006255A (en)
MY (1) MY150508A (en)
PA (1) PA8805901A1 (en)
PE (1) PE20091037A1 (en)
PL (1) PL2222293T3 (en)
PT (1) PT2222293E (en)
RS (1) RS51992B (en)
SI (1) SI2222293T1 (en)
TN (1) TN2010000250A1 (en)
TW (1) TW200930356A (en)
WO (1) WO2009071585A1 (en)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2425835A1 (en) * 2010-08-18 2012-03-07 Grindeks, a joint stock company A new medical use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and natural flavonoid derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI487524B (en) * 2010-12-03 2015-06-11 Tetra Sia Novel therapeutic combinations of nicotinic acid and meldonium

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012233A1 (en) * 2003-08-04 2005-02-10 'joint Stock Company Grindeks' Meldonium salts, method of their preparation and pharmaceutical composition on their basis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012233A1 (en) * 2003-08-04 2005-02-10 'joint Stock Company Grindeks' Meldonium salts, method of their preparation and pharmaceutical composition on their basis

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KARPOV R S ET AL: "CLINICAL AND INSTRUMENT ASSESSMENT OF THE EFFICACY OF TREATING PATIENTS WITH COMBINED ATHEROSCLEROSIS OF THE CORONARY CEREBRAL AND PERIPHERAL ARTERIES", TERAPEVTICHESKII ARKHIV, vol. 63, no. 4, 1991, pages 90 - 93, XP008087626, ISSN: 0040-3660 *
OKUNEVICH I V ET AL: "[Anti-atherosclerotic action of mildronate in experiment]", PATOLOGICHESKAIA FIZIOLOGIIA I ÈKSPERIMENTAL'NAIA TERAPIIA 2002 APR-JUN, no. 2, April 2002 (2002-04-01), pages 24 - 27, XP008087617, ISSN: 0031-2991 *
VEVERIS M ET AL: "Experimental hypercholesterolemia and atherosclerosis model in laboratory mice", BALTIC JOURNAL OF LABORATORY ANIMAL SCIENCE, vol. 10, no. 3-4, 2000, pages 194 - 199, XP008087675, ISSN: 1407-0944 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2425835A1 (en) * 2010-08-18 2012-03-07 Grindeks, a joint stock company A new medical use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and natural flavonoid derivatives

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HRP20110744T1 (en) 2011-11-30
MX2010006255A (en) 2011-03-15
DK2222293T3 (en) 2011-11-21
CA2706354A1 (en) 2009-06-11
PL2222293T3 (en) 2012-01-31
CN101951898A (en) 2011-01-19
TW200930356A (en) 2009-07-16
CL2008003551A1 (en) 2010-01-22
PT2222293E (en) 2011-11-15
PA8805901A1 (en) 2009-07-23
US20100234459A1 (en) 2010-09-16
TN2010000250A1 (en) 2011-11-11
CN101951898B (en) 2012-12-05
ZA201003641B (en) 2011-03-30
CA2706354C (en) 2013-08-13
EP2222293B1 (en) 2011-08-03
EP2222293A1 (en) 2010-09-01
MY150508A (en) 2014-01-30
CO6280477A2 (en) 2011-05-20
BRPI0819057A2 (en) 2015-05-05
CY1112336T1 (en) 2015-12-09
EA201000738A1 (en) 2011-04-29
AR069521A1 (en) 2010-01-27
KR20100084688A (en) 2010-07-27
RS51992B (en) 2012-04-30
IL205961A0 (en) 2010-11-30
MA31993B1 (en) 2011-01-03
DOP2010000163A (en) 2010-08-31
GEP20125673B (en) 2012-10-25
PE20091037A1 (en) 2009-08-19
JP2011505408A (en) 2011-02-24
ATE518536T1 (en) 2011-08-15
SI2222293T1 (en) 2011-12-30
EA019424B1 (en) 2014-03-31
AU2008333262A1 (en) 2009-06-11

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