EP1128823A1 - Use of propionyl l-carnitine for the preparation of a medicament capable of inducing apoptosis - Google Patents

Use of propionyl l-carnitine for the preparation of a medicament capable of inducing apoptosis

Info

Publication number
EP1128823A1
EP1128823A1 EP99956317A EP99956317A EP1128823A1 EP 1128823 A1 EP1128823 A1 EP 1128823A1 EP 99956317 A EP99956317 A EP 99956317A EP 99956317 A EP99956317 A EP 99956317A EP 1128823 A1 EP1128823 A1 EP 1128823A1
Authority
EP
European Patent Office
Prior art keywords
carnitine
propionyl
medicament
acid
treatment
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP99956317A
Other languages
German (de)
English (en)
French (fr)
Inventor
Menotti Calvani
Claudio Pisano
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
Original Assignee
Sigma Tau Industrie Farmaceutiche Riunite SpA
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 PCT/IT1998/000318 external-priority patent/WO2000027386A1/en
Priority claimed from IT1998RM000701A external-priority patent/IT1302858B1/it
Application filed by Sigma Tau Industrie Farmaceutiche Riunite SpA filed Critical Sigma Tau Industrie Farmaceutiche Riunite SpA
Publication of EP1128823A1 publication Critical patent/EP1128823A1/en
Ceased legal-status Critical Current

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
    • 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
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • propionyl L-carnitine for the preparation of a medicament capable of inducing apoptosis.
  • the present invention relates to the use of propionyl L- carnitine and the pharmaceutically acceptable salts thereof for the preparation of medicaments useful in the treatment of pathologies whose treatment gains a benefit from inducement of apoptosis, in particular blood vessels, such as restenosis after angioplasty or coronary stenting, or in particular tumours.
  • proliferation of smooth muscle cells which migrated to intima from vascular tunica media, represents cell basis of coronaric restenosis after rivascularization processes through angioplasty or dilatation by means of a stent.
  • cytostatic drugs such as etoposide (Llera-Moya et al., 1992), with steroid hormones (Cavallero et al.; 1971; 1973; 1975; 1976), progestinic hormones (Spagnoli et al., 1990), dexamethasone (Asai et al., 1993).
  • Smooth muscle cell proliferation is also inhibited by calcium antagonist substances due both to a decrease of DNA synthesis, such as in case of verapamil (Stein et al., 1987) and to the interference in second messenger systems (cAMP), as demonstrated for nifedipine (Cheung et al., 1987).
  • calcium antagonist substances due both to a decrease of DNA synthesis, such as in case of verapamil (Stein et al., 1987) and to the interference in second messenger systems (cAMP), as demonstrated for nifedipine (Cheung et al., 1987).
  • Angioplasty initiates a number of responses in the vessel wall including cellular migration, proliferation, and matrix accumulation, all of which contribute to neointima formation and restenosis (Malik N et al; Circulation 1998 Oct 20; 98(16): 1657-65). Inducing apoptosis may be beneficial also to reverse vascular disease, as pulmonary vascular disease (Cowan K. N. et al. Circ. Res. 1999 May 28; 84(10): 1223-33). Restenosis after angioplasty is due to damaged intima cells. Using apoptosis inducing substances, for example for treating tumors, bears the risk to provoke a generalised phenomenon, with possible side effects, which can be even very severe, such as in the case of stem cells.
  • One of the general problems of pharmacological therapy is the therapeutic index of the agents, that is to say the ratio of the therapeutically effective dose to the toxic dose, or, at any rate, the dose that gives rise to the onset of side effects.
  • the medical community still perceives the need for therapeutic regimens which allow the patient to face up to the treatment, which, in the case of anticancer chemotherapy is particularly hard to support, while at the same time conserving an acceptable quality of life.
  • These considerations also apply to the therapeutic treatment of animals, for instance, so-called pets.
  • propionyl L-carnitine thanks to its unexpected proapoptotic effect, is endowed with a specific action of control on smooth muscular cells of vessels and on tumor cells.
  • Abstract of the invention It is an object of the present invention the use of propionyl L- carnitine and the pharmacologically acceptable salts thereof for the preparation of a medicament useful in the treatment of pathologies whose treatment gains a benefit from inducement of apoptosis, in particular blood vessels, such as restenosis after angioplasty or coronary stenting, or in particular tumors.
  • propionyl L-carnitine does not imply toxic effects on bone marrow and in gut, which have a good production of blood cellular elements and a very good turnover of intestinal mucosa cells, respectively.
  • Propionyl L-carnitine has been described as preventing the progression of atherosclerotic lesions in aged hyperlipemic rats (Spagnoli L.G., Orlandi A., Marino B., Mauriello A., De Angelis C, Ramacci M.T., Atherosclerosis 1995; 1 14, 29-44).
  • the authors demonstrate the strong antiatherogenic effect of propionyl L-carnitine (also named PLC). This effect, although demonstrated in rabbits, admittedly a model not applicable to man, was elucidated through a lipid lowering effect.
  • PLC prevents the progression of atherosclerotic lesions in aged hyperlipemic rabbits acting as hypolipidemic agent.
  • PLC indirectly acts as antiatherogenic agent. No antiproliferative action was demonstrated for PLC.
  • the present invention is based on the application of the discovery that propionyl L-carnitine (hereinafter also named PLC for brevity) induces the phenomenon of programmed death (apoptosis) in the cells.
  • PLC propionyl L-carnitine
  • This effect allows the treatment of blood vessel pathologies based on the proliferation of smooth muscular cells of vessel walls, such as pulmonary hypertension, hypertension, restenosis after angioplasty or coronary stenting.
  • PLC is a well-known drug, whose side effects are quite limited. Examples of use of propionyl l-carnitine are US 4415589, US 4255449, IT 1 155772, EP 0793962, EP 081 1376, W099/ 17623, PCT/IT97/00113.
  • a first aspect of the present invention relates to the use of propionyl L-carnitine and the pharmacologically acceptable salts thereof for the preparation of a medicament useful in the treatment of pathologies whose treatment gains a benefit from inducement of apoptosis, in particular blood vessels, such as restenosis after angioplasty or coronary stenting, or in particular tumors.
  • Another object of the present invention is the use of propionyl L-carnitine and the pharmacologically acceptable salts thereof for the preparation of a medicament useful for the treatment of hypertension.
  • Another object of the present invention is the use of propionyl L-carnitine and the pharmacologically acceptable salts thereof for the preparation of a medicament useful for the treatment of hypertension.
  • Another object of the present invention is the use of propionyl L-carnitine and the pharmacologically acceptable salts thereof for the preparation of a medicament useful for the treatment of hypertension.
  • Another object of the present invention is the use of propionyl
  • L-carnitine and the pharmacologically acceptable salts thereof for the preparation of a medicament useful for the treatment of pulmonary hypertension are included in the preparation of a medicament useful for the treatment of pulmonary hypertension.
  • Still another aspect of the present invention is the use of propionyl L-carnitine and the pharmacologically acceptable salts thereof for the preparation of a medicament useful to prevent restenosis after angioplasty or coronary stenting.
  • an object of the invention described herein is the coordinated use the propionyl L-carnitine according to which an adjuvant effect with the anticancer agent is obtained.
  • adjuvant effect it is intended a combination therapy of an antitumour drug and propionyl L-carnitine, by means of which, PLC exerts an apoptotic effect on the tumour cell, thus assisting the cytotoxic effect of the antitumour drug. In this way an improvement of the therapeutic index of the antitumour drug is expected.
  • a further object of the invention described herein is the use of propionyl L-carnitine in the preparation of a medicament useful for treating tumors.
  • Yet another object of the invention described herein are combinations the propionyl L-carnitine with anticancer agents and the related pharmaceutical compositions.
  • co-ordinated use of the aforesaid compounds is, indifferently, either (i) co-administration, i.e. the substantially simultaneous or sequential administration of propionyl L-carnitine or one of its pharmacologically acceptable salts and of an anticancer agent, or (ii) the administration of a composition comprising the aforesaid active ingredients in combination and in a mixture, in addition to optional pharmaceutically acceptable excipients and/ or vehicles.
  • the invention described herein thus covers both the co- administration of propionyl L-carnitine or one of its pharmacologically acceptable salts and of the anticancer agent, and pharmaceutical compositions, which can be administered orally, parenterally or nasally, including controlled-release forms, comprising the two active ingredients in a mixture.
  • an anticancer agent such as for example, taxol, bleomycin, carboplatin, vincristine, a camptothecine.
  • propionyl L- carnitine can be used in the co-ordinated use.
  • Co-administration also means a package, or manufactured article, comprising distinct administration forms of propionyl L- carnitine or one of its pharmacologically acceptable salts and of an anticancer agent, accompanied by instructions for the co-ordinated simultaneous or time- scheduled 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 embodiment of the invention described herein also contributes to healing and to prolonging the lives of the patients thanks to the increase in therapeutic success due to the possibility of maintaining the scheduled treatment protocols or of increasing the doses of the chemotherapeutic agent, without having to discontinue the treatment due to contraindications. It also possible to foresee a reduction of the dose of the anticancer drug, thanks to the adjuvant effect of propionyl L-carnitine.
  • the medicament according to the present invention can be obtained admixing the active ingredient (propionyl L-carnitine or a pharmacologically acceptable salt thereof) with excipients suitable for formulation of compositions intended for enteral administration (in particular the oral one) or parenteral administration (in particular through intramuscular or intravenous route). All such excipients are well known to persons skilled in the art.
  • active ingredient propionyl L-carnitine or a pharmacologically acceptable salt thereof
  • excipients suitable for formulation of compositions intended for enteral administration (in particular the oral one) or parenteral administration (in particular through intramuscular or intravenous route). All such excipients are well known to persons skilled in the art.
  • pharmaceutically acceptable salt of propionyl L-carnitine it is intended any salt thereof with an acid which does not give rise to unwanted side effects. These acids are well known to the pharmacologists and to the experts of pharmaceutical technology.
  • Non-limiting examples of said salts are chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, lactate, maleate and acid maleate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate.
  • a tablet contains:
  • a bottle contains:
  • a solvent vial contains:
  • the medicament prepared according to the present invention will be administered in the form of pharmaceutical composition, which can be prepared according to the general common knowledge of the person skilled in the art.
  • the pharmaceutical composition will be in the suitable form.
  • suitable form examples of pharmaceutical compositions, wherein the medicament according to the present invention is comprised, are the solid or liquid oral forms, such as tablets, all types of capsules, pills, solutions, suspensions, emulsions in the form of unitary or divided doses, syrups, ready-to-use or extemporary drinkable unit doses.
  • solid or liquid oral forms such as tablets, all types of capsules, pills, solutions, suspensions, emulsions in the form of unitary or divided doses, syrups, ready-to-use or extemporary drinkable unit doses.
  • Other examples are- parenteral forms, injectable forms for intramuscular, subcutaneous or intravenous administration. Controlled or programmed release forms are also appropriate.
  • Dosages, posology and general therapeutic regimen will be determined by the physician according to his knowledge, patient's conditions and the pathology to be treated.
  • the present invention relates to restenosis after angioplasty.
  • the pharmacological dose of PLC is such as not to exceed hematic concentration of 100 mM.
  • EXAMPLE 1 Wistar male rats, weighing between 270 and 290 mg, were used for the experiments.
  • the rats were anaesthetised with Nembutal i.p. (35 mg/kg body weight) and the thoracic portion of aorta was submitted to endothelium mechanical removal with Fogarty 2F balloon probe (Baxter USA), according to the Baugartner and Studer method(1966) with minor modification (Orlandi 1994).
  • the animals were randomized into 5 groups, each group is reported in Table 1.
  • the animals were sacrificed 3 and 15 days after deendothelialization. Two hours before sacrifice, all the rats received i.v. a Bromodeoxyuridine solution (BrDU) (45 mg/kg body weight) in order to verify cell proliferation. One hour before sacrifice, some randomly selected animals received 1 ml Blue Evans (1% in 0.9% NaCl solution) in order to evaluate the degree of aorta disruption.
  • BrDU Bromodeoxyuridine solution
  • the animals were anaesthetised with i.p. Nembutal and perfused, after washing with isotonic saline containing 3% Dextran 70, with buffered formalin for 20 minutes.
  • Aortae were isolated, slightly washed in saline and dissected longitudinally. Carotid, heart and small intestine were also excised. All the organs were post-fixed in the same fixative for 24 hours at room temperature. Some aortic fragments were used for electronic microscopy.
  • Aortae were rolled up and included in paraffin. Serial sections having 5 ⁇ m thickness were stained with Hematoxylin-Eosine, Verhoeff-Van Gieson and Movat's pentachromic and used for morphologic and morphometric studies. In some non-perfused animals, fragments of aortic tissue were frozen in liquid nitrogen for the determination of tissular carnitines and for subsequent studies of molecular biology.
  • the reaction was evidenced by using diaminobenzidine (DAB) as final chromogen.
  • DAB diaminobenzidine
  • the count of positive nuclei for BrDU was made on the total number of nuclei. Such count was blind-made by two researchers separately. The difference between the two counts was always lower than 0.5%.
  • Plasma samples 2-3 ml blood samples were withdrawn from each animal before mechanical de-endothelialization and just before sacrifice. Plasma was separated by centrifugation (3000 rpm) for 20 minutes and frozen for the plasmatic carnitine assay according to the Pace et al. method.
  • rat aortae did not show significant hystological alterations, except the lack of endothelial cell coating.
  • BrDU staining positive nuclei showed substantial differences between the two groups examined. Quantitative analysis (Table 2) puts in evidence that the number of BrDU-positive nuclei is significantly lower in the tunica media in the PLC-treated animals, with respect to controls (59.3% reduction against control, p ⁇ 0.02). In both groups the distribution of BrDU-positive nuclei is more concentrated in the lumen portion of mean tunica with respect to the adventitia portion, with a 2: 1 ratio. b) 15 days after de-endothelialization: Table 3 shows that in each group the proliferation index of SMCs is significantly higher (p ⁇ 0.001) in the intima with respect to the tunica media. No significant differences are observed in the number of BrDU-positive nuclei, in the intima and tunica media, by comparing PLC, Enalapril and control animals.
  • intima vs tunica media p ⁇ 0.0001 ;
  • intima vs tunica media p ⁇ 0.0001 ;
  • ⁇ c) intima vs tunica media p ⁇ 0.001 ;
  • intima vol. /wall vs controls p ⁇ 0.02;
  • intima vol/ wall vs controls p ⁇ 0.01 EFFECT OF PROPIONYL L-CARNITINE IN THE CONTROL
  • Table 4 cell number/ ml at culture days 2, 3, 4 and 6
  • Human derived neoplastic cell obtained from Istituto Zooprofilattico of Brescia, were cultivated.
  • the cells used for the experiment were: U266, multiple myleopma, HeLa, uterine cervix tumor, K562, chronic myeloid leukemia cells.
  • HeLa and K562 were cultivated in RPMI+ 10% FCS, while those of U266 line were cultivated in RPMI+ 15% FCS, both media containing Penicilline/Streptomycine (50 U/mL and 50 ⁇ g/mL).
  • Cells were plated in 6-wells plates (Falcon). Analysis were performed in cells having 50% confluence.
  • Each cell line was treated with PCL according to the folowing schemes: a) 1 mM PLC for 24 hours (figures 1-3); 1 mM PLC for 48 hours (figures 1-3); b) 1 mM PLC for 24 hours, followed by 24 hours media without molecules (figures 4-6).
  • PLC inhibition effect persists after having removed the substances from cultivation medium. In fact, in this case cells werer treated for 24 hours with 1 nM PLC, then the medium contining PLC was removed and fresh medium was added without the substance. Inhibition values were 20%, 26% and 21% for HeLa, U266 and K562, respectively.
  • Cavallero C De Lellis C, Di Tondo U. et al. In: Cavallero C, editor. The arterial wall in atherogenesi. Padova: Piccin Medical Book, 1975: 25-42
  • Negoro N. Inariba H., Inoue T., Kanayama Y., Takeda T.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP99956317A 1998-11-11 1999-11-09 Use of propionyl l-carnitine for the preparation of a medicament capable of inducing apoptosis Ceased EP1128823A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
PCT/IT1998/000318 WO2000027386A1 (en) 1998-11-11 1998-11-11 Use of propionylcarnitine for the manufacture of a medicament for inhibiting smooth muscle cell proliferation
WOPCT/IT98/00318 1998-11-11
IT1998RM000701A IT1302858B1 (it) 1998-11-11 1998-11-11 Uso della l-carnitina e dei suoi alcanoil derivati per la preparazionedi un medicamento avente attivita' antitumorale.
ITRM980701 1998-11-11
PCT/IT1999/000357 WO2000027387A1 (en) 1998-11-11 1999-11-09 Use of propionyl l-carnitine for the preparation of a medicament capable of inducing apoptosis

Publications (1)

Publication Number Publication Date
EP1128823A1 true EP1128823A1 (en) 2001-09-05

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP99956317A Ceased EP1128823A1 (en) 1998-11-11 1999-11-09 Use of propionyl l-carnitine for the preparation of a medicament capable of inducing apoptosis

Country Status (6)

Country Link
EP (1) EP1128823A1 (enExample)
JP (1) JP2002529408A (enExample)
KR (1) KR100694004B1 (enExample)
AU (1) AU1294600A (enExample)
CA (1) CA2350071A1 (enExample)
WO (1) WO2000027387A1 (enExample)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101006207B1 (ko) * 2008-09-25 2011-01-07 김형호 잡음차단수단을 갖는 헤드셋

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1254314B (it) * 1992-03-27 1995-09-14 Sigma Tau Ind Farmaceuti Composizioni farmaceutiche conyenenti l-carnitina e acil- carnitine inassociazione con ace-inibitori per il trattamento di patologie cardiovascolari.
EP0681839A3 (en) * 1994-05-12 1997-11-12 Hirohiko Kuratsune A pharmaceutical preparation comprising an acylcarnitine
US5786326A (en) * 1995-02-03 1998-07-28 Horwitz; Lawrence D. Method for the treatment of atherosclerosis and vascular injury by prevention of vascular smooth muscle cell proliferation
IT1276253B1 (it) * 1995-12-15 1997-10-27 Sigma Tau Ind Farmaceuti Composizione farmaceutica contenente l-carnitina o alcanoil l-carnitine per la prevenzione ed il trattamento di stati morbosi
DK0793962T3 (da) * 1996-03-04 2000-05-22 Sigma Tau Ind Farmaceuti Lægemiddel indeholdende et carnitinderivat til behandling af arteriosclerosis obliterans
IT1283951B1 (it) * 1996-03-15 1998-05-07 Mendes Srl Uso della acetil l-carnitina o dei suoi sali farmacologicamente accettabili per il trattamento terapeutico o la profilassi di

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0027387A1 *

Also Published As

Publication number Publication date
KR20010080379A (ko) 2001-08-22
AU1294600A (en) 2000-05-29
CA2350071A1 (en) 2000-05-18
JP2002529408A (ja) 2002-09-10
WO2000027387A1 (en) 2000-05-18
KR100694004B1 (ko) 2007-03-12

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