WO1997006795A1 - Compositions pharmaceutiques a base de gamma-butyrobetaine pour le traitement des troubles de la circulation sanguine - Google Patents

Compositions pharmaceutiques a base de gamma-butyrobetaine pour le traitement des troubles de la circulation sanguine Download PDF

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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
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
active principle
pharmaceutically acceptable
blood
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Application number
PCT/LV1996/000003
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English (en)
Inventor
Ivars Kalvinsh
Maris Veveris
Original Assignee
Ivars Kalvinsh
Maris Veveris
Priority date (The priority date 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 date listed.)
Filing date
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Application filed by Ivars Kalvinsh, Maris Veveris filed Critical Ivars Kalvinsh
Publication of WO1997006795A1 publication Critical patent/WO1997006795A1/fr

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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

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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques à base de η-butyrobétaïne pour administration orale, parentérale, sous-cutanée ou rectale, destinées au traitement des troubles de la circulation sanguine de diverses origines et localisations. En expérimentation, cette composition administrée in vivo à raison de 10mg/kg à des chats anesthésiés, fait remonter le débit sanguin total de 12 %, sans changement notable de la tension artérielle et du rythme cardiaque. Cette composition bloque les spasmes induits par l'adrénaline au niveau des vaisseaux sanguins d'une oreille isolée de lapin. Lorsqu'elle est administrée à une concentration de 2,0 mM, cette composition fait baisser de 18 % la pression de reperfusion. Le blocage de la NO-synthétase inverse l'effet de la composition sur les spasmes induits par l'adrénaline au niveau des vaisseaux sanguins. Administrée en perfusion à raison de 200mg/kg, la composition fait monter de façon significative le taux de coagulation sanguine pendant les phases I-II. Dans le cas d'expériences comparatives, la composition de l'invention fait preuve d'un effet plus puissant que celui obtenu avec un médicament connu [3-(2,2,2-triméthylhydrazinium) propionate]. La composition est remarquable pour sa faible toxicité et sa grande marge de sécurité.
PCT/LV1996/000003 1995-08-21 1996-08-20 Compositions pharmaceutiques a base de gamma-butyrobetaine pour le traitement des troubles de la circulation sanguine WO1997006795A1 (fr)

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)

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WO1997006795A1 true WO1997006795A1 (fr) 1997-02-27

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000051596A1 (fr) * 1999-03-02 2000-09-08 Jallal Messadek La glycine betaïne pour son usage antithrombotique
WO2002062322A2 (fr) * 2001-02-05 2002-08-15 Jallal Messadek Glycine-betaine et utilisation correspondante
WO2003022262A1 (fr) * 2001-09-07 2003-03-20 Ivars Kalvinsh Composition pharmaceutique contenant de la gamma-butyrobetaine
WO2004049095A2 (fr) * 2002-11-25 2004-06-10 Jallal Messadek Compositions de betaine
WO2005012233A1 (fr) * 2003-08-04 2005-02-10 'joint Stock Company Grindeks' Sels de meldonium, leur procede de preparation et compositions pharmaceutiques les contenant
JP2007500705A (ja) * 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 化合物
WO2006050585A3 (fr) * 2004-11-10 2007-03-22 Jallal Messadek Modulation de synthases d'oxyde nitrique par des 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)

* Cited by examiner, † Cited by third party
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 (ja) * 1988-02-23 1989-08-28 Kyowa Hakko Kogyo Co Ltd カルニチンおよびカルニチンアミドの精製法
US5030458A (en) * 1989-11-27 1991-07-09 Shug Austin L Method for preventing diet-induced carnitine deficiency in domesticated dogs and cats

Patent Citations (5)

* Cited by examiner, † Cited by third party
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 (ja) * 1988-02-23 1989-08-28 Kyowa Hakko Kogyo Co Ltd カルニチンおよびカルニチンアミドの精製法
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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7608640B2 (en) 1999-03-02 2009-10-27 Jallal Messadek Glycine betaine and its use
BE1012495A3 (fr) * 1999-03-02 2000-11-07 Messadek Jallal La glycine-betaine pour son usage antithrombotique.
WO2000051596A1 (fr) * 1999-03-02 2000-09-08 Jallal Messadek La glycine betaïne pour son usage antithrombotique
KR100767270B1 (ko) * 1999-03-02 2007-10-17 잘랄 메사덱 글리신 베타인의 항혈전성 용도
US6855734B2 (en) 1999-03-02 2005-02-15 Jallal Messadek Glycine betaine and its use
WO2002062322A2 (fr) * 2001-02-05 2002-08-15 Jallal Messadek Glycine-betaine et utilisation correspondante
WO2002062322A3 (fr) * 2001-02-05 2002-11-28 Jallal Messadek Glycine-betaine et utilisation correspondante
WO2003022262A1 (fr) * 2001-09-07 2003-03-20 Ivars Kalvinsh Composition pharmaceutique contenant de la gamma-butyrobetaine
AU2002236340B2 (en) * 2001-09-07 2008-06-12 Anatolijs Birmans Pharmaceutical composition comprising gamma-butyrobetaine
WO2004049095A3 (fr) * 2002-11-25 2004-12-23 Jallal Messadek Compositions de betaine
WO2004049095A2 (fr) * 2002-11-25 2004-06-10 Jallal Messadek Compositions de betaine
US8343947B2 (en) 2003-07-15 2013-01-01 Jallal Messadek Therapeutic treatment
JP2007500705A (ja) * 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 化合物
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 (ko) * 2003-08-04 2007-08-01 조인트 스탁 컴퍼니 그린덱스 멜도늄 염, 그것의 제조방법 및 그것을 주성분으로 한약학적 조성물
EA009083B1 (ru) * 2003-08-04 2007-10-26 Акционерное Общество "Гриндекс" Соли мелдония, способ их получения и фармацевтические композиции на их основе
JP2007501222A (ja) * 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” メルドニウム（Ｍｅｌｄｏｎｉｕｍ）塩、メルドニウム塩の調製方法、およびメルドニウム塩を主成分とする薬学的組成物
WO2005012233A1 (fr) * 2003-08-04 2005-02-10 'joint Stock Company Grindeks' Sels de meldonium, leur procede de preparation et compositions pharmaceutiques les contenant
WO2006050585A3 (fr) * 2004-11-10 2007-03-22 Jallal Messadek Modulation de synthases d'oxyde nitrique par des 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

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Publication number Publication date
LV11727B (en) 1997-08-20
LV11727A (lv) 1997-04-20

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