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WO2006061341A1 - Utilisation de propionyl l-carnitine pour la preparation d'un medicament fortement dose pour le traitement de maladie arterielle peripherique - Google Patents

Utilisation de propionyl l-carnitine pour la preparation d'un medicament fortement dose pour le traitement de maladie arterielle peripherique Download PDF

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Publication number
WO2006061341A1
WO2006061341A1 PCT/EP2005/056323 EP2005056323W WO2006061341A1 WO 2006061341 A1 WO2006061341 A1 WO 2006061341A1 EP 2005056323 W EP2005056323 W EP 2005056323W WO 2006061341 A1 WO2006061341 A1 WO 2006061341A1
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WIPO (PCT)
Prior art keywords
carnitine
propionyl
acid
treatment
medicament
Prior art date
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Ceased
Application number
PCT/EP2005/056323
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English (en)
Inventor
Aleardo Koverech
Francesco Violi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sigma Tau Industrie Farmaceutiche Riunite SpA
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Sigma Tau Industrie Farmaceutiche Riunite SpA
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Application filed by Sigma Tau Industrie Farmaceutiche Riunite SpA filed Critical Sigma Tau Industrie Farmaceutiche Riunite SpA
Publication of WO2006061341A1 publication Critical patent/WO2006061341A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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 invention described herein relates to the use of propionyl L- carnitine for the preparation of a medicament for the treatment of peripheral arterial disease.
  • Peripheral arterial disease is caused by atherosclerosis of the leg arteries and is usually complicated by vascular accidents occurring not only in peripheral circulation but also in cerebral and coronary trees. Approximately one third of patients with PAD suffers from claudication, that usually deteriorates slowly: 25% of patients have worsening claudication and about 5% experience amputation within 5 years.
  • Ankle/arm pressure ratio is a non invasive test which may help to identify patients at high risk of cardiovascular events.
  • An ankle/brachial index (ABI) ⁇ 0.8 is predictive of cardiovascular events and significantly increased the risk of peripheral vascular complications including surgical intervention, or angioplasty or local thrombolysis (Violi, F., et al., Atherosclerosis 1996,120:25-35).
  • the risk of peripheral vascular complications is even higher with ankle/arm pressure ratio worsening, as documented by an even more elevated risk of peripheral vascular deterioration in patients with ABI ⁇ 0.5 (Dormandy, JA; Murray, GD; Eur. J. Vase. Surg., 1991;5:131-3).
  • Brevetti et al. studies provide a limited teaching to the oral administration of L-carnitine or propionyl L-carnitine to a daily dose of 2 g.
  • Brevetti et al. (Circulation, 1988; 77:767-73) demonstrated that in six claudicant patients intravenously treated with 3 g L-carnitine as a bolus followed by infusion of 2 mg/Kg/man for 30 minutes the increase of venous lactate induced by walking test was lowered; but it was not reported if this treatment had some effects on walking distance or ABI.
  • the present invention provides an improvement in the treatment of peripheral arterial disease (PAD) by dramatically shortening the period of treatment. Moreover, in spite of the high dosage used according to the present invention, no serious adverse or side effects were observed, thus further improving patients' compliance.
  • PAD peripheral arterial disease
  • the present invention improves the ABI parameter, thus giving an indication not only of increased walking distance, namely improving symptoms and making better the patient's quality of life, but especially decreasing the risk of peripheral vascular complications.
  • propionyl L-carnitine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a patient suffering from peripheral arterial disease at least at stage II of the Leriche- Fontaine's classification, wherein said medicament is suitably formulated for the administration of about 4 to about 8 g/day of propionyl L-carnitine by intravenous route.
  • Propionyl L-carnitine is a well-known compound, currently available on the market or it can be easily prepared with well-known methods.
  • the preparation of propionyl L-carnitine and its pharmaceutically acceptable salts is disclosed, for example, in the patent literature in the name of the applicant.
  • Examples of pharmaceutically acceptable salts of propionyl L-carnitine are chloride, bromide, orotate, acid aspartate, acid citrate, magnesium citrate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, mucate, acid oxalate, pamoate, acid pamoate, acid sulfate, glucose phosphate, tartrate, acid tartrate, magnesium tartrate, 2 -amino ethansulfonate, magnesium 2- amino ethansulfonate, choline tartrate and trichloroacetate.
  • the present invention is applied to patients suffering from peripheral arterial disease with a moderate to severe grade.
  • Reference to the grade is made to the Leriche-Fontaine's classification, see the above mentioned US patent 5,811,457.
  • the patient may not suffer rest pain; however, the medicament according to the present invention can be advantageously used, in order to prevent a worsening of the disease.
  • the patient is at risk of amputation; in this case the medicament herein disclosed can be used in order to prevent a dramatic outcome of the disease.
  • the medicament of the present invention is used in patients having a walking autonomy lower than 200 meters and an ABI lower than 0,6.
  • said medicament is in the form of a preparation for infusion and said infusion lasts about 8 hours.
  • the person skilled in the art will decide the effective time of administration, depending on the patient's conditions, degree of severity of the disease, response of the patient and any other clinical parameter within the general knowledge of this matter.
  • the high dose of propionyl L-carnitine ranges from about 4 to about 8 g/days, preferably about 6 g/days.
  • the infusion is suitable for the administration of about 750 mg/hour of propionyl L- carnitine or of an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the treatment normally lasts about 7 days, the length of treatment being decided by the skilled person, as per the duration of the infusion discussed above.
  • the dosage can be adjusted around the indicated values depending on the patient's conditions, degree of the disease and any other element evaluated in the normal practice in this field.
  • the medicament is in the form of a package suitable for 7 days treatment. This can be particularly advantageous for non- hospitalized, home-cared patients.
  • This preparation can be obtained with procedures commonly used in the art.
  • a guidance for the preparation of the intravenous infusion can be found in technical literature, see for example Remington's Pharmaceutical Science Handbook, the last edition, or regulatory textbooks, such as European Pharmacopoeia.
  • Treadmill test was performed using a treadmill speed of 3.5 km/h at 12% grade until maximal claudication pain.
  • ABI was calculated, as previously described (Hiatt WR., N. Engl. J. Med., 2001; 344:1608-1621), with the patient placed in the supine position, measuring the higher systolic pressure of the anterior tibial or posterior tibial artery in each limb and dividing this pressure with the highest brachial systolic pressure. In patients with diabetes we performed toe pressure determinations. ABI measurement was obtained 5 minutes before the exercise.
  • ABI measurement and treadmill exercise were performed at baseline and at day 8, 12 hours after the final infusion of propionyl-1-carnitine.
  • NO levels were evaluated through the measurement of metabolic end products (Calbiochem nitrite/nitrate assay), i.e. nitrite and nitrate, using enzymatic catalysis coupled with Griess reaction as reported by Verdon (Anal. Biochem., 1995; 224:502-508).
  • Clinical characteristics of patients are the following: 95% of the patients were hypertensive, 50% had dyslipidemia, 50% were diabetics and 40% smokers (no current users but ex-users of cigarettes). Forty and 25% of patients had had a clinical history of coronary heart disease (CHD) and cerebrovascular disease respectively. Concomitant treatments included: anticoagulants (10%), anti-platelets agents (95%), anti-hypertensive treatment (ACE-inhibitors 55%, Calcium antagonists 45%, doxazosin 10%, diuretics 55%), metformin 30%, insulin 20%, statins 45%. Diabetes mellitus was defined according to the American Diabetic Association new criteria and as the use of insulin or oral hypoglicemic drugs (Diabetes Care, 1997; 20:1183-1197).
  • Hypertension was defined according to the criteria of the Sixth Joint National Committee Report on the Detection, Evaluation and Treatment of Hypertension or in subjects who were currently taking antihypertensive medication ⁇ Arch. Intern. Med.; 1997; 157:2413- 2444).
  • Dyslipidemia was defined according to the criteria of the Third Report of the National Cholesterol Education Program or in subjects who were currently taking lipid lowering drugs ⁇ JAMA; 2001; 285: 2486-2497).
  • Ischaemic heart disease was defined on the basis of history and medical records. Current smokers were defined as patients smoking at least five cigarettes a day.
  • Baseline values of MWD and ABI were 54.75 ⁇ 39.03 meters and 0.48 ⁇ 0.09 respectively; after seven days of treatment MWD and ABI significantly increased to 104.1 ⁇ 58.58 meters (p ⁇ 0.001) and to 0.6 ⁇ 0.089 (p ⁇ 0.001) respectively at paired samples T test; these figures corresponded to 90% increase of MWD and to 25% increase of ABI.
  • the clinical efficacy was equally distributed among diabetic and non- diabetic patients.
  • propionyl L-carnitine was also analysed in accordance to the Rutherford classification. At baseline, 17 were in II class and 3 in III class; after treatment 10 were in II class and 10 in III class. In patients of group 2 NO plasma levels were measured at baseline and 12 hours after the final infusion of propionyl L-carnitine; compared to baseline values a significant increase of NO was found after propionyl L-carnitine treatment (19.95 ⁇ 4.9 ⁇ mol/L vs 28.29 ⁇ 5.7 ⁇ mol/L; pO.001).
  • propionyl L-carnitine infusion After propionyl L-carnitine infusion, according to the present invention, there was a lesser number of patients who had severe claudication (85% at baseline vs 50% after treatment).
  • the preparation for intravenous infusion is obtained by any conventional method generally known in the art, for example as provided in the European Pharmacopoeia or United States Pharmacopoeia.
  • the active ingredient can be formulated in an injectable composition, to be diluted into saline at the suitable concentration.
  • injectable formulation can be an injectable solution of the active ingredient or a lyophilized form of the same.
  • injectable solution is the following:

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation de propionyl L-carnitine ou d'un de ses sels pharmaceutiquement acceptables pour la préparation d'un médicament convenant au traitement d'un patient souffrant de maladie artérielle périphérique au moins au stade II de la classification de Leriche-Fontaine, ledit médicament étant formulé de façon à convenir à l'administration de propionyl L-carnitine dans une dose comprise entre environ 4 à 8 g/jour, de préférence 6 g/jour, ou par voie intraveineuse. L'invention concerne également une préparation pour infusion intraveineuse convenant à l'administration de propionyl L-carnitine. Cette invention permet de mieux traiter la maladie et d'augmenter le paramètre ABI, à savoir d'améliorer des symptômes et d'offrir une meilleure qualité de vie au patient et permet en particulier de diminuer le risque de complications vasculaires périphériques.
PCT/EP2005/056323 2004-12-10 2005-11-29 Utilisation de propionyl l-carnitine pour la preparation d'un medicament fortement dose pour le traitement de maladie arterielle peripherique Ceased WO2006061341A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04425913.3 2004-12-10
EP04425913 2004-12-10

Publications (1)

Publication Number Publication Date
WO2006061341A1 true WO2006061341A1 (fr) 2006-06-15

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PCT/EP2005/056323 Ceased WO2006061341A1 (fr) 2004-12-10 2005-11-29 Utilisation de propionyl l-carnitine pour la preparation d'un medicament fortement dose pour le traitement de maladie arterielle peripherique

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WO (1) WO2006061341A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110217252A1 (en) * 2008-11-11 2011-09-08 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Compound useful for treating cellulite

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4343816A (en) * 1979-02-12 1982-08-10 Claudio Cavazza Pharmaceutical composition comprising an acyl-carnitine, for treating peripheral vascular diseases
US4968719A (en) * 1989-04-03 1990-11-06 Sigma Tau, Industrie Farmaceutiche Riunite Spa Method for treating vascular disease
US5811457A (en) * 1996-03-04 1998-09-22 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Therapeutical method for treating chronic arteriosclerosis obliterans
WO2000027386A1 (fr) * 1998-11-11 2000-05-18 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Procede d'utilisation de la l-carnitine de propionyle pour fabriquer un medicament destine a inhiber la proliferation des cellules musculaires lisses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4343816A (en) * 1979-02-12 1982-08-10 Claudio Cavazza Pharmaceutical composition comprising an acyl-carnitine, for treating peripheral vascular diseases
US4968719A (en) * 1989-04-03 1990-11-06 Sigma Tau, Industrie Farmaceutiche Riunite Spa Method for treating vascular disease
US5811457A (en) * 1996-03-04 1998-09-22 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Therapeutical method for treating chronic arteriosclerosis obliterans
WO2000027386A1 (fr) * 1998-11-11 2000-05-18 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Procede d'utilisation de la l-carnitine de propionyle pour fabriquer un medicament destine a inhiber la proliferation des cellules musculaires lisses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STRANO, ANTONIO: "Propionyl-L-carnitine versus pentoxifylline: improvement in walking capacity in patients with intermittent claudication", CLINICAL DRUG INVESTIGATION, vol. 22-Suppl.1, 2002, pages 1 - 6, XP008046870 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110217252A1 (en) * 2008-11-11 2011-09-08 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Compound useful for treating cellulite

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