WO2000074675A1 - Combinaisons antilipemiques comprenant des inhibiteurs de hmg-coa reductase et des carnitines - Google Patents

Combinaisons antilipemiques comprenant des inhibiteurs de hmg-coa reductase et des carnitines Download PDF

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Publication number
WO2000074675A1
WO2000074675A1 PCT/EP2000/005091 EP0005091W WO0074675A1 WO 2000074675 A1 WO2000074675 A1 WO 2000074675A1 EP 0005091 W EP0005091 W EP 0005091W WO 0074675 A1 WO0074675 A1 WO 0074675A1
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WO
WIPO (PCT)
Prior art keywords
carnitine
alkanoyl
statin
acid
simvastatin
Prior art date
Application number
PCT/EP2000/005091
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English (en)
Inventor
Arduino Arduini
Alessandro Peschechera
Paolo Carminati
Original Assignee
Sigma-Tau Industrie Farmaceutiche S.P.A.
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
Publication date
Priority claimed from EP99830415A external-priority patent/EP1064943B1/fr
Application filed by Sigma-Tau Industrie Farmaceutiche S.P.A. filed Critical Sigma-Tau Industrie Farmaceutiche S.P.A.
Priority to CA002375378A priority Critical patent/CA2375378C/fr
Priority to JP2001501212A priority patent/JP2003501385A/ja
Priority to AU59697/00A priority patent/AU782188B2/en
Priority to SK1715-2001A priority patent/SK285900B6/sk
Priority to PL352106A priority patent/PL197899B1/pl
Priority to MXPA01012644A priority patent/MXPA01012644A/es
Publication of WO2000074675A1 publication Critical patent/WO2000074675A1/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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention described herein relates to a pharmaceutical composition for the treatment of diseases caused by lipid metabolism disorders, and in particular a pharmaceutical composition comprising a statin and L-carnitine or one of its alkanoyl derivatives, useful for the prevention and treatment of statin-induced toxic or side effects.
  • Cardiovascular diseases related to lipid metabolism disorders are very frequent in the industrialised countries. In Italy, for instance, they account for more than 40% of the overall mortality (Capocaccia R., Farchi G., Prati S. et al.: La mortalita' in Italia nell'anno 1989. Rapporto ISTISAN 1992/22).
  • Our knowledge of the relationships between cholesterol and coronary heart disease stems from epidemiological studies conducted in recent years. The conclusions of these studies indicate that the development of severe coronary atherosclerosis is closely related to serum cholesterol levels (McGill H.C. Jr. et al.: The International Atherosclerosis Project. Lab. Invest. 18: 463-653, 1968; Keys A.: Seven countries: Death and Coronary Heart Disease. Harvard University Press, Cambridge, 1980).
  • This category includes both drugs that prevalently reduce cholesterol levels and drugs that prevalently reduce triglyceride levels.
  • the former group of drugs includes statins, probucol and resins, and the latter group fibrates, nicotinic acid and omega-3- series fatty acids.
  • statins are hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. By inhibiting this enzyme, they reduce the hepatic synthesis of cholesterol (Lancet 1994; 334: 1383- 1389). To compensate for the reduction in intracellular cholesterol, the liver cell produces more receptors for lipoproteins of the LDL and VLDL series, which in this way are removed from the bloodstream.
  • HMG-CoA hydroxy-methylglutaryl coenzyme A
  • statins cause less absorption of cholesterol of dietary origin in the intestine and a reduced output of apoprotein B present in low-density lipoproteins (LDL).
  • LDL low-density lipoproteins
  • statins are better tolerated than the other cholesterol- lowering agents, but present certain drawbacks: the most common side effects caused by these drugs are gastrointestinal disorders, skin rashes and headache.
  • EP 0383432 describes the combination of an HMG-CoA reductase inhibitor and coenzyme QIO for the treatment of skeletal muscle myopathy caused by statins.
  • statins cause a reduction in the number of deaths due to coronary heart disease, but, on the other hand, an increase in deaths due to other events such as tumours or trauma has been noted in treated patients (Davey-Smith G., Song
  • the co-ordinated use according to the invention is particularly useful and safe for the treatment of both hypercholesterolaemic and/ or hyper- triglyceridaemic patients at high risk for cardiovascular disease in the short, medium or long term.
  • co- administration is also a pack or manufactured article, comprising distinct administration forms of L-carnitine or one of the aforesaid alkanoyl L-carnitines, or one of their pharmacologically acceptable salts and a statin, accompanied by instructions for the co-ordinated simultaneous intake of the active ingredients according to a dosage regimen established by the primary care physician on the basis of the patient's condition.
  • the invention described herein therefore covers both the co- administration of L-carnitine or one of the aforesaid alkanoyl L- carnitines, or one of their pharmacologically acceptable salts and a statin, and pharmaceutical compositions which can be administered orally or parenterally, comprising a mixture of the two active ingredients.
  • a further subject of the invention described herein is the use of a detoxifying amount of L-carnitine or an alkanoyl L-carnitine, in which the linear of branched alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable salts, for the preparation of a medicinal agent useful for the treatment of statin-induced toxic or side effects.
  • the invention described herein also comprises the use of L- carnitine or an alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-6 carbon atoms, or of one of their pharmacologically acceptable salts, for the preparation of a medicinal agent useful for the treatment of statin-induced toxic or side effects.
  • the statin is preferably selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin
  • the alkanoyl L-carnitine is preferably selected from the group consisting of acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or one of their pharmacologically acceptable salts.
  • the statin is simvastatin and the alkanoyl L- carnitine is propionyl L-carnitine or one of its pharmacologically acceptable salts.
  • statin is simvastatin and the carnitine is L-carnitine or one of its pharmacologically acceptable salts.
  • a pharmacologically acceptable salt of an alkanoyl L-carnitine is any salt of this with an acid which does not give rise to toxic or side effects. These acids are well known to pharmacologists and to experts in pharmaceutical technology.
  • Examples of pharmaceutically acceptable salts of alkanoyl L- carnitines are chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid maleate, mucate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate.
  • the combination according to the invention allows better treatment of diseases related to lipid metabolism disorders, thus achieving greater therapeutic success.
  • the combination according to the invention also contributes to the healing and to prolonging the lives of the patients treated, amongst other things thanks to the increase in therapeutic success rates due to the possibility of maintaining the scheduled treatment protocols for longer periods, without having to discontinue the treatment owing to the toxic or side effects of the statins.
  • mice Male Wister rats aged 23 days and weighing 45-50 g were used. The animals were housed in polycarbonate cages, 5 animals per cage, maintained at a constant temperature of 22 ⁇ 2°C and at 55 + 15% relative humidity, with a light-darkness cycle of 12 hours, fed on 4RF21 pellet feed (Mucedola), with tap water to drink ad libitum.
  • the control group consisted of 14 animals, whereas the groups treated with simvastatin at various doses and with simvastatin plus L-carnitine consisted of 10 animals each, according to the following experimental design:
  • L-carnitine was given by oral administration via a gastric tube, twice daily (2 x 200 mg/kg) suspended in 0.5% carboxymethylcellulose (CMC) to the groups treated with statin, or in water when administered alone.
  • CMC carboxymethylcellulose
  • Simvastatin was administered orally suspended in 0.5% carboxy-methylcellulose (CMC) (10 mL/kg). The duration of the treatment was 9 days.
  • CMC carboxy-methylcellulose
  • the blood was centrifuged at 400 rpm for 30 min and the serum thus obtained was used to evaluate plasma levels of CK, GOT, GPT and cholesterol.
  • the CK, GOT, GPT and cholesterol analyses were carried out using a Cobas Mira S (Roche) automatic analyser and Roche diagnostic kits. Since the plasma enzyme activity showed a highly skewed distribution, it was decided to analyse the data using the non- parametric Mann-Whitney U test; the test data are shown as median values together with the associated ranges.
  • the cholesterol level was significantly lowered only at the highest simvastatin dose used.
  • the administration of L-carnitine to the groups treated with simvastatin showed lower plasma CK activity compared to the group treated with simvastatin alone.
  • L-carnitine administration was significantly effective in counterbalancing the plasma CK elevation at the simvastatin doses of 140 and 210 mg/kg (Table 1).
  • a further realisation of the invention described herein comprises the co-ordinated use of L-carnitine or one of its alkanoyl derivatives or one of their pharmacologically acceptable salts and of a statin according to the above definitions, in the treatment of animals, such as, for example, livestock and, particularly, pets.
  • L-carnitine, or one of its derivatives may be in solid form, such as, for example, fumarate, tartrate or mucate, to be dissolved in drinking water, or in metered- dose liquid form, to be diluted.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Diabetes (AREA)
  • Toxicology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique. Cette composition comprend un produit abaissant le taux de lipides, comme la lovastatine, la simvastatine, la pravastatine et la fluvastatine et la L-carnitine ou L-carnitine alcanoyle. Cette composition présente l'avantage de conserver l'efficacité d'un produit abaissant le taux de lipides et d'être sensiblement dépourvu d'effets toxiques ou d'effets secondaires propres à ce type de médicaments.
PCT/EP2000/005091 1999-06-08 2000-06-05 Combinaisons antilipemiques comprenant des inhibiteurs de hmg-coa reductase et des carnitines WO2000074675A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002375378A CA2375378C (fr) 1999-06-08 2000-06-05 Combinaisons antilipemiques comprenant des inhibiteurs de hmg-coa reductase et des carnitines
JP2001501212A JP2003501385A (ja) 1999-06-08 2000-06-05 Ｈｍｇ−ｃｏａレダクターゼ阻害剤とカルニチン類を含む抗高脂血症性組合せ
AU59697/00A AU782188B2 (en) 1999-06-08 2000-06-05 Antilipemic combinations comprising HMG-COA reductase inhibitors and carnitines
SK1715-2001A SK285900B6 (sk) 1999-06-08 2000-06-05 Použitie L-karnitínu alebo alkanoyl L-karnitínu na prípravu lieku na liečenie toxických alebo vedľajších účinkov vyvolaných inhibítorom HMG-CoA reduktázy
PL352106A PL197899B1 (pl) 1999-06-08 2000-06-05 Zastosowanie przeciwlipemiczne środka zawierającego statyny i karnityny
MXPA01012644A MXPA01012644A (es) 1999-06-08 2000-06-05 Combinaciones antilipemicas que comprenden inhibidores de hmg-coa reductasa y carnitina.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US13800899P 1999-06-08 1999-06-08
US60/138,008 1999-06-08
EP99830415.8 1999-06-30
EP99830415A EP1064943B1 (fr) 1999-06-30 1999-06-30 Combinaison ayant une activité hypolipémiante substantiellement dénuée des effets toxiques ou effets secondaires causés par les médicaments à activité hypolipémiante

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WO2000074675A1 true WO2000074675A1 (fr) 2000-12-14

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JP (1) JP2003501385A (fr)
KR (1) KR100725263B1 (fr)
AU (1) AU782188B2 (fr)
CA (1) CA2375378C (fr)
CZ (1) CZ20014218A3 (fr)
HU (1) HUP0201597A3 (fr)
MX (1) MXPA01012644A (fr)
PL (1) PL197899B1 (fr)
SK (1) SK285900B6 (fr)
WO (1) WO2000074675A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104239A1 (fr) * 2007-02-27 2008-09-04 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Composition à utiliser pour le traitement du diabète de type 2
WO2008113862A2 (fr) * 2007-03-21 2008-09-25 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Composition utile pour la prévention du diabète de type 2 et de ses complications dans des patients pré-diabétiques présentant une résistance à l'insuline
WO2009105853A2 (fr) 2008-02-29 2009-09-03 Biolab Sanus Farmaceutica Ltda. Composition pharmaceutique
JP2012110714A (ja) * 2010-11-24 2012-06-14 Fujitsu Ltd スタチン誘発性ミオパシー及び他の医的障害のセンサベースの診断

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JPS62126126A (ja) * 1985-11-28 1987-06-08 Snow Brand Milk Prod Co Ltd 経腸栄養剤
EP0383432A1 (fr) * 1989-01-18 1990-08-22 Merck & Co. Inc. Coenzyme Q10 avec inhibiteurs de HMG-COA réductase
WO1999001126A1 (fr) * 1997-07-01 1999-01-14 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Compositions pharmaceutiques comprenant alcanoyle l-carnitine en combinaison avec une statine pour traiter des pathologies resultant d'un metabolisme lipidique altere

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JPS62126126A (ja) * 1985-11-28 1987-06-08 Snow Brand Milk Prod Co Ltd 経腸栄養剤
EP0383432A1 (fr) * 1989-01-18 1990-08-22 Merck & Co. Inc. Coenzyme Q10 avec inhibiteurs de HMG-COA réductase
WO1999001126A1 (fr) * 1997-07-01 1999-01-14 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Compositions pharmaceutiques comprenant alcanoyle l-carnitine en combinaison avec une statine pour traiter des pathologies resultant d'un metabolisme lipidique altere

Non-Patent Citations (4)

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Title
BHUIYAN ET AL.: "The effects of 3-Hydroxy-3-Methylglutaryl-CoA reductase inhibition on tissue levels of carnitine and carnitine acyltransferase activity in the rabbit", LIPIDS, vol. 31, no. 8, 1996, pages 867 - 870, XP000872223 *
DATABASE MEDLINE [online] NLM, Bethesda, USA; XP002081551, retrieved from DIALOG accession no. 07446723 Database accession no. 92217262 *
PATENT ABSTRACTS OF JAPAN vol. 011, no. 353 (C - 457) 18 November 1987 (1987-11-18) *
SAVICA ET AL.: "[The hypotriglyceridemic action of the combination of L-carnitine + simvastatin vs. L-carnitine and vs. simvastatin]", CLIN. TER., vol. 140, no. 1 Pt 2, January 1992 (1992-01-01), pages 17-22 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA016855B1 (ru) * 2007-02-27 2012-08-30 Сигма-Тау Индустрие Фармасьютике Риуните С.П.А. Применение l-карнитина и/или алканоил l-карнитина в комбинации со статином для лечения диабета 2 типа
KR101699430B1 (ko) * 2007-02-27 2017-01-24 시그마타우 인두스트리에 파르마슈티케 리우니테 에스.피.에이. ２형 당뇨의 치료에 유용한 조성물
WO2008104239A1 (fr) * 2007-02-27 2008-09-04 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Composition à utiliser pour le traitement du diabète de type 2
AU2007348123B2 (en) * 2007-02-27 2013-01-17 Alfasigma S.P.A. Composition useful for the treatment of type 2 diabetes
KR20090115939A (ko) * 2007-02-27 2009-11-10 시그마타우 인두스트리에 파르마슈티케 리우니테 에스.피.에이. ２형 당뇨의 치료에 유용한 조성물
CN101663030B (zh) * 2007-03-21 2013-08-21 希格马托制药工业公司 可用于预防患有胰岛素耐受的前驱糖尿病患者的2型糖尿病及其并发症的组合物
US8389574B2 (en) 2007-03-21 2013-03-05 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Method useful for the prevention of type 2 diabetes and its complications in pre-diabetic patients with insulin resistance
WO2008113862A3 (fr) * 2007-03-21 2008-12-31 Sigma Tau Ind Farmaceuti Composition utile pour la prévention du diabète de type 2 et de ses complications dans des patients pré-diabétiques présentant une résistance à l'insuline
EA018442B1 (ru) * 2007-03-21 2013-08-30 Сигма-Тау Индустрие Фармасьютике Риуните С.П.А. Применение l-карнитина для лечения гипертензии, для снижения систолического или пульсового давления крови у субъектов с предиабетом
WO2008113862A2 (fr) * 2007-03-21 2008-09-25 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Composition utile pour la prévention du diabète de type 2 et de ses complications dans des patients pré-diabétiques présentant une résistance à l'insuline
EP2262495A2 (fr) * 2008-02-29 2010-12-22 Biolab Sanus Farmacéutica Ltda Composition pharmaceutique comprenant du racetam et de la carnitine et son procede de preparation
EP2262495A4 (fr) * 2008-02-29 2012-01-11 Biolab Sanus Farmaceutica Ltda Composition pharmaceutique comprenant du racetam et de la carnitine et son procede de preparation
KR20100126454A (ko) * 2008-02-29 2010-12-01 바이오랩 세너스 팔마씨우티카 엘티디에이. 라세탐 및 카르니틴을 포함하는 약학 조성물 및 그의 제조방법
WO2009105853A2 (fr) 2008-02-29 2009-09-03 Biolab Sanus Farmaceutica Ltda. Composition pharmaceutique
AU2009219050B2 (en) * 2008-02-29 2014-04-24 Biolab Sanus Farmaceutica Ltda. Pharmaceutical composition comprising racetam and carnitine and process for its preparation
KR101686917B1 (ko) * 2008-02-29 2016-12-15 바이오랩 세너스 팔마씨우티카 엘티디에이. 라세탐 및 카르니틴을 포함하는 약학 조성물 및 그의 제조방법
JP2012110714A (ja) * 2010-11-24 2012-06-14 Fujitsu Ltd スタチン誘発性ミオパシー及び他の医的障害のセンサベースの診断

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KR20020025066A (ko) 2002-04-03
AU5969700A (en) 2000-12-28
PL352106A1 (en) 2003-07-28
MXPA01012644A (es) 2002-07-22
HUP0201597A3 (en) 2003-04-28
KR100725263B1 (ko) 2007-06-07
CZ20014218A3 (cs) 2002-04-17
AU782188B2 (en) 2005-07-07
HUP0201597A2 (en) 2002-09-28
JP2003501385A (ja) 2003-01-14
PL197899B1 (pl) 2008-05-30
CA2375378A1 (fr) 2000-12-14
SK285900B6 (sk) 2007-10-04
CA2375378C (fr) 2009-08-11
SK17152001A3 (sk) 2002-03-05

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