WO1997006795A1 - Pharmaceutical compositions containing gamma-butyrobetain for treatment of blood flow disorders - Google Patents
Pharmaceutical compositions containing gamma-butyrobetain for treatment of blood flow disorders Download PDFInfo
- Publication number
- WO1997006795A1 WO1997006795A1 PCT/LV1996/000003 LV9600003W WO9706795A1 WO 1997006795 A1 WO1997006795 A1 WO 1997006795A1 LV 9600003 W LV9600003 W LV 9600003W WO 9706795 A1 WO9706795 A1 WO 9706795A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- composition according
- active principle
- pharmaceutically acceptable
- blood
- Prior art date
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
- A61K31/185—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
Definitions
- the present invention relates to pharmaceutical compositions, namely to the pharmaceutical compositions which are providing for treatment of blood flow disturbances of various genesis and localisation.
- the therapeutic composition contains the known chemical substance, the novel action of which gives unexpected pharmacological effects, namely, there is disclosed pharmaceutical composition which contains ⁇ -butyrobetaine as an active principle in a combination with pharmaceutically acceptable fillers and/or solvents.
- ⁇ -Butyrobetaine (actinine), from which the mammalian organism synthesises carnitine, was primarily characte ⁇ sed as a toxic substance which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and heart stop in diastole (W.Linneweh, Z.Physiol.Chem., 42,181,1929).
- ⁇ -butyrobetaine is extremely low toxic (LD S0 7000 mg/kg, s.c).
- Literature lacks the data on cardiovascular effects of ⁇ - butyrobetaine, though it was reported (Hosein E.A., McLennan H. Pharmacological action of ⁇ - butyrobetaine. Nature, 1956, 183, 328-329) j that butyrobetaine is a substance similar to acetyl choline with a
- ⁇ -betaine aza-analog - 3-(2,2,2- trimethylhydrazinium)propionate (Mildronate, Quaterine). Its mechanism of action is based on limitation of carnitine biosynthesis rate and related long- chain fatty acid transport decrease through mitochondria membranes [Simkhovich B.Z., Shutenko Z.V., Meirena D.V. et al. 3-(2,2,2- trimethylhydrazinium)propionate (THP) - a novel ⁇ -butyrobetaine inhibitor with cardioprotective properties. Biochem. Pharmacol. 1988, 37, 195-202].
- the cardiovascular activity and the toxicity of pharmaceutical compositions containing ⁇ -butyrobetaine was determined. Acute toxicity was evaluated on male and female mice (19-26 g), 10 animals in a group. The substances were administered in the form of 10% solution in water or in isotonic solution orally or intravenously (with 0.004 ml/sec rate, if i.v.). It was established that at oral administration LD 50 of ⁇ - butyrobetaine is >4500 mg/kg, but at intravenous injection LD 5 o is 1860(1430-2418) mg/kg, which testifies that ⁇ -butyrobetaine is practically non-toxic substance.
- Substance Dose i.v., Blood Pulse rate Blood flow mg/kg pressure changes rate changes, % changes, %
- the chest was opened in the experimental animals, they were artificially respirated, and blood pressure in the carotid artery as well as general aorta blood flow were measured on physiograph DMP-4B of "Narco
- ⁇ -butyrobetaine effect on the blood flow was connnected with earlier erroneously attributed cholinergic component which, mainly relates to ⁇ -butyrobetaine ester (The Merck Index, Eleventh Edition, 1871) impurities in the samples of insufficiently purified ⁇ - butyrobetaine, then one would anticipate a significant decrease in the blood pressure and heart rate (see acetyl choline effect, Table I).
- the observed cardiovascular effect indicates a positive inotropic effect of the proposed therapeutic composition with simultaneous peripheral resistance decrease by a completely another mechanism, which can be used in the treatment of low heart potency and of blood circulation disturbances of various genesis.
- Substance Systolic pressure (mm Hg) max/min Decrease concentra of the tion ( uM) sxstolic pressure
- ⁇ -Butyrobetaine also affects blood coagulation time. This was determined in male ICE-JCL albino mice (24-28 g), 10 mice in a group, using Moravic's method (Thodorov Y. Khlinicheskye laboratomie issledovania v pediatrii, Medic. Phys.”, Sophia, 1966, p.p.479-480, in Russian). Time when fibrin strings develop was determined. The blood was sampled from jugular vein, mice were preliminarily anaesthetized with urethane (1000 mg/kg, i.p.). The solutions ofthe substances were infusively administered directly before detection ofthe blood coagulation time.
- Table 4 shows that ⁇ -butyrobetaine considerably prolongs blood coagulation I-II phase, i.e. the time when fibrin strings develop. This means that pharmaceutical compositions on the butyrobetaine basis can be applied in the therapy of such blood circulation failures which are connected with thrombus formation and thrombus embolia.
- Table 4 Influence of ⁇ -butyrobetaine (GBB) on blood coagulation time in mice (after Moravica)
- the pharmaceutical composition on the basis of ⁇ -butyrobetaine possesses a wide spectrum of vascular action which is connected with its effect on blood vessel and miocardium tonus as well on NO-synthase, being more potent than known preparation Mildronate which is a close ⁇ -butyrobetaine structural analogue.
- the pharmaceutical composition containing ⁇ - butyrobetaine is a promising agent for the treatment of blood flow disturbances of various genesis.
- the preparation can be administered both orally, parenterally, rectally or transcutaneously.
- the pharmaceutical composition contains ⁇ -butyrobetaine in the total amount of 0.5 to 40% by weight, and as a pharmaceutically acceptable solvent - distilled water, isotonic or glucose or buffer solution.
- the active principle is administered orally or sublingually in tablets, caplets, dragee, granules, powders or capsules they contain ⁇ - butyrobetaine in total amount of 0.01 to 0.5 g in a tablet, caplet, dragee, capsule or in one portion of powder or granule.
- the active principle are administered transcutaneously its content in an ointment or plaster makes up 0.5 to 40%) by weight.
- the active principle is administered rectally its content in a suppository or microenema accounts for 0.5 to 40% by weight.
Abstract
The invention relates to η-butyrobetaine-containing pharmaceutical compositions for oral, parenteral, subcutaneous or rectal administrations, that are providing for the treatment blood circulation disturbances of various genesis and localisation. This composition in the experiments on anaesthesized cats at a dose of 10 mg/kg, i.v. increases the total blood flow by 12 %, not considerably changing blood pressure and heart rhythm. The composition arrests adrenaline-induced isolated rabbit ear blood-vessel spasms. In a concentration of 2.0 mM it decreases reperfusion pressure by 18 %. NO-synthase blocking reverses the composition effect on adrenaline-caused blood-vessel spasms. Being infused the composition at a dose of 200 mg/kg significantly increases blood coagulation during phases I-II. In the comparative experiments the disclosed composition demonstrates more potent effect compared to known medicine [3-(2,2,2-trimethylhydrazinium)propionate]. The preparation is distinguished by a low toxicity and wide safety margin.
Description
f
DESCRIPTION
PHARMACEUTICAL COMPOSITIONS CONTAINING GAMMA-BUTYROBETAIN FOR TREATMENT OF BLOOD FLOW DISORDERS
TECHNICAL FIELD
The present invention relates to pharmaceutical compositions, namely to the pharmaceutical compositions which are providing for treatment of blood flow disturbances of various genesis and localisation. The therapeutic composition contains the known chemical substance, the novel action of which gives unexpected pharmacological effects, namely, there is disclosed pharmaceutical composition which contains γ-butyrobetaine as an active principle in a combination with pharmaceutically acceptable fillers and/or solvents.
BACKGROUND ART γ-Butyrobetaine (actinine), from which the mammalian organism synthesises carnitine, was primarily characteπsed as a toxic substance which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and heart stop in diastole (W.Linneweh, Z.Physiol.Chem., 42,181,1929). At the same time, in later papers other authors ascertained that γ-butyrobetaine is extremely low toxic (LDS0 7000 mg/kg, s.c). (W.Rotzsch, L.Lorenz,E.Strack, Acta biol.med.ger. 1959, 3, 28-36). Literature lacks the data on cardiovascular effects of γ- butyrobetaine, though it was reported (Hosein E.A., McLennan H. Pharmacological action of γ- butyrobetaine. Nature, 1956, 183, 328-329) j that butyrobetaine is a substance similar to acetyl choline with a
.
prolonged action. However, later the same authors reported that by an error the experiments involved, instead of γ- butyrobetaine, its methyl esther which in fact possesses cholinergic properties. Contrary to the former γ-butyrobetaine was characterised as a pharmacologically inert substance (E.A.Hoseln, P.Proulx, Isolation and probable functions of betaine esters in brain metabolism, Nature, 1960, 187, 321-322. A.S.V.Burgen, F.Hobiger. Brit.J.Pharmacol., 1949, 4, 229. E.Strack, K.Foesterling. Z. Physiol. Chem., 1953,295, 377
The closest structural analogue of γ-butyrobetaine which is used for the treatment of cardiovascular diseases is γ-betaine aza-analog - 3-(2,2,2- trimethylhydrazinium)propionate (Mildronate, Quaterine). Its mechanism of action is based on limitation of carnitine biosynthesis rate and related long- chain fatty acid transport decrease through mitochondria membranes [Simkhovich B.Z., Shutenko Z.V., Meirena D.V. et al. 3-(2,2,2- trimethylhydrazinium)propionate (THP) - a novel γ-butyrobetaine inhibitor with cardioprotective properties. Biochem. Pharmacol. 1988, 37, 195-202].
DISCLOSURE OF THE INVENTION
The cardiovascular activity and the toxicity of pharmaceutical compositions containing γ-butyrobetaine was determined. Acute toxicity was evaluated on male and female mice (19-26 g), 10 animals in a group. The substances were administered in the form of 10% solution in water or in isotonic solution orally or intravenously (with 0.004 ml/sec rate, if i.v.). It was established that at oral administration LD50 of γ- butyrobetaine is >4500 mg/kg, but at intravenous injection LD5o is 1860(1430-2418) mg/kg, which testifies that γ-butyrobetaine is practically non-toxic substance. Special experiments on cats demonstrated that the pharmaceutical compositions containing purified γ-butyrobetaine at a dose 186 times lower than toxic possesses a stronger effect on blood vessel tonus and blood flow than the known preparation and closest structural analogue Mildronate, and, contrary to acetyl choline, there are not observed blood pressure decrease and heart rate decline, while blood flow essentially increases (Table 1).
Table 1. Influence of 3-(2,2,2-trimethylhydrazine)propionate (M), γ- buryrobetaine (GBB) and acetylcholine (Ach) on haemodynamics in anaesthesized cats
Substance Dose, i.v., Blood Pulse rate Blood flow mg/kg pressure changes rate changes, % changes, %
M 5.0 - 3 - 3 + 5
M 10.0 - 5 - 3 + 8*
GBB 5.0 - 4 - 5 + 6
GBB 10.0 -7 - +3 - 5 + 12"
Ach 0.001 -35* -20* - 8
" p<0.05 vs the initial parameters **p<0.05 vs the corresponding M dose
The experiments were performed on male and female (2.9-3.8 kg) anaesthetised cats (urethane (200mg/kg) and chloralose (50 mg/kg), both i.p.).
The chest was opened in the experimental animals, they were artificially respirated, and blood pressure in the carotid artery as well as general aorta blood flow were measured on physiograph DMP-4B of "Narco
Bio-Systems", USA.
If the observed γ-butyrobetaine effect on the blood flow was connnected with earlier erroneously attributed cholinergic component which, mainly relates to γ-butyrobetaine ester (The Merck Index, Eleventh Edition, 1871) impurities in the samples of insufficiently purified γ- butyrobetaine, then one would anticipate a significant decrease in the blood pressure and heart rate (see acetyl choline effect, Table I). The observed cardiovascular effect indicates a positive inotropic effect of the proposed therapeutic composition with simultaneous peripheral resistance decrease
by a completely another mechanism, which can be used in the treatment of low heart potency and of blood circulation disturbances of various genesis. In the experiments with isolated rabbit ear blood vessels the pharmaceutical composition which contains γ-butyrobetaine was 2-3 times more potent in adrenaline-induced blood vessel spasm than the closest structural analogue - the known preparation 3-(2,2,2- trimethylhydrazinium)propionate (M).
Table 2. Influence of 3-(2,2,2-trimethylhydrazine)propionate (M) and γ- butyrobetaine (GBB) on the blood vessels spasms induced by adrenaline in the isolated rabbit's ear
Substance Systolic pressure (mm Hg) max/min Decrease concentra of the tion ( uM) sxstolic pressure,
%
Initial parameters Parameters after adrenaline injection 3.10 "
M mav min max min
M, 0.3 38±5 8±2 125 80 1
M, 1.0 38±5 8±2 123 77 4
M.2.0 38±5 8±2 126 80 8*
GBB, 0.3 38±5 8±2 124 76 6
GBB, 1.0 38±5 8±2 125 80 15*
GBB, 2.0 38±5 8±2 125 78 18
* p<0.05 **p<0.01
It was unexpectedly discovered that in the basis of this vasodilating effect lies NO-synthase activation which is completely blocked by L-N02-arginine (Table 3).
Table 3. Influence of 3-(2,2,2-trimetlιylhydrazine)propionate (M) and γ- butyrobetaine (GBB) on the blood vessels spasms induced by adrenaline in the presence of L-nitroarginine (L-N0 -Arg) (10 mg/1) in the isolated rabbit's ear
γ-Butyrobetaine also affects blood coagulation time. This was determined in male ICE-JCL albino mice (24-28 g), 10 mice in a group, using Moravic's method (Thodorov Y. Khlinicheskye laboratomie issledovania v pediatrii, Medic. Phys.", Sophia, 1966, p.p.479-480, in Russian). Time when fibrin strings develop was determined. The blood was sampled from jugular vein, mice were preliminarily anaesthetized with urethane (1000 mg/kg, i.p.). The solutions ofthe substances were infusively administered directly before detection ofthe blood coagulation time. Table 4 shows that γ-butyrobetaine considerably prolongs blood coagulation I-II phase, i.e. the time when fibrin strings develop. This means that pharmaceutical compositions on the butyrobetaine basis can be applied in the therapy of such blood circulation failures which are connected with thrombus formation and thrombus embolia.
Table 4. Influence of γ-butyrobetaine (GBB) on blood coagulation time in mice (after Moravica)
Substance, dose (mg/kg) Coagulation time <sec)
GBB, 200 mg/kg, injection 46 + 5.5*
Control (isotonic solution) 23.75 +3.4
'p<0.05
Thus, we have unexpectedly discovered that the pharmaceutical composition on the basis of γ-butyrobetaine possesses a wide spectrum of vascular action which is connected with its effect on blood vessel and miocardium tonus as well on NO-synthase, being more potent than known preparation Mildronate which is a close γ-butyrobetaine structural analogue. Hence, the pharmaceutical composition containing γ- butyrobetaine is a promising agent for the treatment of blood flow disturbances of various genesis. The preparation can be administered both orally, parenterally, rectally or transcutaneously.
In the case the active principle is administered as injection or orally in the form of drops, syrup or drink the pharmaceutical composition contains γ-butyrobetaine in the total amount of 0.5 to 40% by weight, and as a pharmaceutically acceptable solvent - distilled water, isotonic or glucose or buffer solution.
In the case the active principle is administered orally or sublingually in tablets, caplets, dragee, granules, powders or capsules they contain γ- butyrobetaine in total amount of 0.01 to 0.5 g in a tablet, caplet, dragee, capsule or in one portion of powder or granule.
In the case the active principle are administered transcutaneously its content in an ointment or plaster makes up 0.5 to 40%) by weight. In the case the active principle is administered rectally its content in a suppository or microenema accounts for 0.5 to 40% by weight.
Claims
1. A pharmaceutical composition for the treatment of blood flow disturbances, which contains γ-butyrobetaine as an active principle and pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to Claim 1 , wherein the composition contains 0.5-95% of γ-butyrobetaine by weight.
3. The pharmaceutical composition according to Claim 1 or 2 wherein it is intended for oral or sublingual administration and is in the form of tablets (with or without a cover), capsules, caplets, dragees, granules, powder or solution, which contain 0.01-0.5g of active principle by weight in every tablet, capsule, dragee, granule or powder dose, or also this is a 0.5-40% solution or syrup for oral administration.
4. The pharmaceutical composition according to Claim 3, wherein the acceptable carrier is selected from the group of substances which consist of stearinic acid and its salts, lactose, glucose, saccharose, starch, talc, vegetable oils, polyethylene glycols, microcrystalline cellulose, aerosil, aromatizers, flavoring agents, colorants, ethyl alcohol and water, which are taken separately or are used in combinations.
5. The pharmaceutical composition according to Claim 1, wherein it is designed for parenteral administration and it has a solution form for injections, which contain 0.5-40% of the active principle by weight and pharmaceutically acceptable solvent.
6. The pharmaceutical composition according to Claim 5, wherein a pharmaceutically acceptable solvent is selected from the group of solvents which contain a distilled water, isotonic solution, buffer solution or glucose solution, which are taken separately or are used in combinations.
7. The pharmaceutical composition according to Claim 1 or 2, wherein it is intended for transcutaneous administration of the active
principle and it is in the form of ointment, solution or plaster, which contains 0.5-40% of the active principle by weight and pharmaceutically acceptable carrier.
8. The pharmaceutical composition according to Claim 7, wherein the pharmaceutically acceptable carrier is chosen from the group which consists of water, polyethylene glycols 400, 1500 and 4000, vegetable oils, fats, glycerine, preservants, emulgators, stabilisers, porous polymer material, dimethylsulphoxide, alcohol and water which are taken separately or are used in combinations.
9. The pharmaceutical composition according to Claim 1 or 2, wherein the it is meant for rectal administration ofthe active principle in the form of suppositories or microenema, which contain 0.5-40% of the active principle by weight and pharmaceutically acceptable carrier.
10. The pharmaceutically composition according to Claim 9, wherein the pharmaceutically acceptable carrier is selected from the groups which consists of water, polyethylene glycols 400, 1500 and 4000, vegetable oils, fats, glycerine, preservants, emulgators and stabilisers, which are taken separately or used in combinations.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LV950255A LV11727B (en) | 1995-08-21 | 1995-08-21 | Pharmaceutical composition |
LVP-95-255 | 1995-08-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997006795A1 true WO1997006795A1 (en) | 1997-02-27 |
Family
ID=19736012
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/LV1996/000003 WO1997006795A1 (en) | 1995-08-21 | 1996-08-20 | Pharmaceutical compositions containing gamma-butyrobetain for treatment of blood flow disorders |
Country Status (2)
Country | Link |
---|---|
LV (1) | LV11727B (en) |
WO (1) | WO1997006795A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000051596A1 (en) * | 1999-03-02 | 2000-09-08 | Jallal Messadek | Antithrombotic use of glycine betaine |
WO2002062322A2 (en) * | 2001-02-05 | 2002-08-15 | Jallal Messadek | Glycine betaine and its use as anti-hemorrhagic agent |
WO2003022262A1 (en) * | 2001-09-07 | 2003-03-20 | Ivars Kalvinsh | Pharmaceutical composition comprising gamma-butyrobetaine |
WO2004049095A2 (en) * | 2002-11-25 | 2004-06-10 | Jallal Messadek | Betaine and salicylic acid compositions |
WO2005012233A1 (en) * | 2003-08-04 | 2005-02-10 | 'joint Stock Company Grindeks' | Meldonium salts, method of their preparation and pharmaceutical composition on their basis |
JP2007500705A (en) * | 2003-07-28 | 2007-01-18 | スミスクライン ビーチャム コーポレーション | Compound |
WO2006050585A3 (en) * | 2004-11-10 | 2007-03-22 | Jallal Messadek | Modulation of nitric oxide synthases by betaines |
US7608640B2 (en) | 1999-03-02 | 2009-10-27 | Jallal Messadek | Glycine betaine and its use |
US7780990B2 (en) | 2005-02-15 | 2010-08-24 | Jallal Messadek | Combination therapeutic compositions and method of use |
US7786077B2 (en) | 2005-04-27 | 2010-08-31 | Jallal Messadek | Insulins combinations |
US8343947B2 (en) | 2003-07-15 | 2013-01-01 | Jallal Messadek | Therapeutic treatment |
US20140088125A1 (en) * | 2011-04-27 | 2014-03-27 | Jsc Grindeks | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4382092A (en) * | 1981-01-06 | 1983-05-03 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Pharmaceutical composition comprising gamma-butyrobetaine for the treatment of syndromes induced by L-carnitine deficiency |
US4451485A (en) * | 1981-09-17 | 1984-05-29 | Institu Organicheskogo Sinteza Akademii Nauk Latviiskoi Ssr | Treatment of cardio-vascular diseases with 3-(2,2,2-trimethylhydrazinium) propionate dihydrate |
US4474812A (en) * | 1982-10-29 | 1984-10-02 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Pharmaceutical composition for improving the biochemical and behavioral parameters of senility |
JPH01213259A (en) * | 1988-02-23 | 1989-08-28 | Kyowa Hakko Kogyo Co Ltd | Purification of carnitine and carnitine amide |
US5030458A (en) * | 1989-11-27 | 1991-07-09 | Shug Austin L | Method for preventing diet-induced carnitine deficiency in domesticated dogs and cats |
-
1995
- 1995-08-21 LV LV950255A patent/LV11727B/en unknown
-
1996
- 1996-08-20 WO PCT/LV1996/000003 patent/WO1997006795A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4382092A (en) * | 1981-01-06 | 1983-05-03 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Pharmaceutical composition comprising gamma-butyrobetaine for the treatment of syndromes induced by L-carnitine deficiency |
US4451485A (en) * | 1981-09-17 | 1984-05-29 | Institu Organicheskogo Sinteza Akademii Nauk Latviiskoi Ssr | Treatment of cardio-vascular diseases with 3-(2,2,2-trimethylhydrazinium) propionate dihydrate |
US4474812A (en) * | 1982-10-29 | 1984-10-02 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Pharmaceutical composition for improving the biochemical and behavioral parameters of senility |
JPH01213259A (en) * | 1988-02-23 | 1989-08-28 | Kyowa Hakko Kogyo Co Ltd | Purification of carnitine and carnitine amide |
US5030458A (en) * | 1989-11-27 | 1991-07-09 | Shug Austin L | Method for preventing diet-induced carnitine deficiency in domesticated dogs and cats |
Non-Patent Citations (2)
Title |
---|
DATABASE WPI Section Ch Week 8940, Derwent World Patents Index; Class B05, AN 89-289767, XP002017003 * |
E.STRACK ET AL.: "L-Karnitin als Basis cholinomimetischer Substanzen", ACTA BIOL. MED. GERM., vol. 35, no. 5, 1976, pages 645 - 656, XP002017002 * |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7608640B2 (en) | 1999-03-02 | 2009-10-27 | Jallal Messadek | Glycine betaine and its use |
BE1012495A3 (en) * | 1999-03-02 | 2000-11-07 | Messadek Jallal | Glycine betaine-for its use antithrombotic. |
WO2000051596A1 (en) * | 1999-03-02 | 2000-09-08 | Jallal Messadek | Antithrombotic use of glycine betaine |
KR100767270B1 (en) * | 1999-03-02 | 2007-10-17 | 잘랄 메사덱 | Antithrombotic use of glycine betaine |
US6855734B2 (en) | 1999-03-02 | 2005-02-15 | Jallal Messadek | Glycine betaine and its use |
WO2002062322A2 (en) * | 2001-02-05 | 2002-08-15 | Jallal Messadek | Glycine betaine and its use as anti-hemorrhagic agent |
WO2002062322A3 (en) * | 2001-02-05 | 2002-11-28 | Jallal Messadek | Glycine betaine and its use as anti-hemorrhagic agent |
WO2003022262A1 (en) * | 2001-09-07 | 2003-03-20 | Ivars Kalvinsh | Pharmaceutical composition comprising gamma-butyrobetaine |
AU2002236340B2 (en) * | 2001-09-07 | 2008-06-12 | Anatolijs Birmans | Pharmaceutical composition comprising gamma-butyrobetaine |
WO2004049095A3 (en) * | 2002-11-25 | 2004-12-23 | Jallal Messadek | Betaine and salicylic acid compositions |
WO2004049095A2 (en) * | 2002-11-25 | 2004-06-10 | Jallal Messadek | Betaine and salicylic acid compositions |
US8343947B2 (en) | 2003-07-15 | 2013-01-01 | Jallal Messadek | Therapeutic treatment |
JP2007500705A (en) * | 2003-07-28 | 2007-01-18 | スミスクライン ビーチャム コーポレーション | Compound |
US7223797B2 (en) | 2003-08-04 | 2007-05-29 | Joint Stock Company “Grindeks” | Meldonium salts, method of their preparation and pharmaceutical composition on their basis |
KR100745160B1 (en) * | 2003-08-04 | 2007-08-01 | 조인트 스탁 컴퍼니 그린덱스 | Meldonium salts, method of their preparation and pharmaceutical composition on their basis |
EA009083B1 (en) * | 2003-08-04 | 2007-10-26 | Акционерное Общество "Гриндекс" | Meldonium salts, method of their preparation and pharmaceutical composition on their basis |
JP2007501222A (en) * | 2003-08-04 | 2007-01-25 | “ジョイント ストック カンパニー グリンデクス” | Meldonium salt, method for preparing meldonium salt, and pharmaceutical composition based on meldonium salt |
WO2005012233A1 (en) * | 2003-08-04 | 2005-02-10 | 'joint Stock Company Grindeks' | Meldonium salts, method of their preparation and pharmaceutical composition on their basis |
WO2006050585A3 (en) * | 2004-11-10 | 2007-03-22 | Jallal Messadek | Modulation of nitric oxide synthases by betaines |
US8318805B2 (en) | 2004-11-10 | 2012-11-27 | Jallal Messadek | Modulation of nitric oxide synthases by betaines |
US7780990B2 (en) | 2005-02-15 | 2010-08-24 | Jallal Messadek | Combination therapeutic compositions and method of use |
US7786077B2 (en) | 2005-04-27 | 2010-08-31 | Jallal Messadek | Insulins combinations |
US20140088125A1 (en) * | 2011-04-27 | 2014-03-27 | Jsc Grindeks | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
AU2012247467B2 (en) * | 2011-04-27 | 2016-07-28 | Grindeks, A Joint Stock Company | Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
US20180079728A1 (en) * | 2011-04-27 | 2018-03-22 | Jsc Grindeks | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
US10351534B2 (en) | 2011-04-27 | 2019-07-16 | Jsc Grindeks | Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
Also Published As
Publication number | Publication date |
---|---|
LV11727B (en) | 1997-08-20 |
LV11727A (en) | 1997-04-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1997006795A1 (en) | Pharmaceutical compositions containing gamma-butyrobetain for treatment of blood flow disorders | |
Calne et al. | Idiopathic Parkinsonism treated with an extracerebral decarboxylase inhibitor in combination with levodopa | |
JPH027572B2 (en) | ||
US5059712A (en) | Isolating aminoarginine and use to block nitric oxide formation in body | |
US5859056A (en) | Pharmaceutical composition for treating cardiovascular diseases containing 3-(2,2,2-trimethylhydrazinium)propionate and γ-butyrobetaine | |
JP2729333B2 (en) | Pharmaceutical compositions for treating conditions requiring vasodilator therapy | |
US20230263761A1 (en) | Agent for elevating nitric oxide concentration | |
JP2012526151A (en) | Allylpropionic acid-based vitamin C stearate, preparation method thereof and drug containing the same | |
IE52404B1 (en) | Pharmaceutical composition comprising gamma-butyrobetaine for the treatment of syndromes induced by l-carnitine deficiency | |
JPH08231390A (en) | Medicine composition containing carnitines | |
US4315944A (en) | Pharmaceutical composition comprising L-carnitine for the treatment of hyperlipidaemias and hyperlipoproteinaemias | |
US6653349B1 (en) | Composition for the prevention and treatment of kidney dysfunctions and diseases | |
CN101070338A (en) | Tanshinone IIA potassium sulfonate used for preparing medicine for preventing and treating cerebral ischemia and cerebral anoxia and myocardial ischemia and myocardio anoxia | |
IE51711B1 (en) | Carnitine derivatives | |
JP3130295B2 (en) | Preventive and / or therapeutic agent for pyruvate deficiency and / or hyperlactic acidemia | |
US20020002202A1 (en) | Use of fumarate salt of L-carnitine or its alkanoyl derivatives in ischaemia | |
AU2001241031B2 (en) | Composition for the prevention and/or treatment of the cytotoxic effects induced by the use of immunosuppressive agents | |
Hayward | The Cardiac Risk in Anaesthesia and Surgery | |
RU2359668C1 (en) | Method of correction of endothelial dysfunction by phosphogliv preparation at l-name induced deficiency of nitrogen oxide | |
JPH03115220A (en) | Arrhythmia preventing medicine derived from non-heart | |
AU2001241031A1 (en) | Composition for the prevention and/or treatment of the cytotoxic effects induced by the use of immunosuppressive agents | |
IE51712B1 (en) | Pharmaceutical compositions containing carnitine derivatives | |
JPH03251541A (en) | Vasodilator |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP UA US AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
122 | Ep: pct application non-entry in european phase |