KR20010080379A - Use of propiony L-carnitine for the preparation of a medicament capable of inducing apoptosis - Google Patents

Abstract

The present invention provides propionyl L-carnitine and pharmaceuticals thereof, in particular for the preparation of a medicament useful for the treatment of pathologies which benefit from the induction of apoptosis of blood vessels, for example, stenosis after angioplasty or coronary stenting, or especially tumors. To an acceptable salt.

Description

Use of propiony L-carnitine for the preparation of a medicament capable of inducing apoptosis

Cell proliferation in circulatory diseases

Numerous studies have demonstrated that cell proliferation plays a pivotal role in the development of atherosclerosis, hypertension and stenosis after angioplasty or coronary stenting (Ross, 1976; Schwartz, 1990).

Numerous experimental studies performed on atherosclerotic plaques in humans have demonstrated that cell proliferation is a decisive phenomenon in both the initial state and progression phase of the plaques.

Moreover, the proliferation of smooth muscle cells that migrate from the vascular intima to the endometrium indicates the cellular mechanism of coronary stenosis after vasodilation through angioplasty or vasodilation by stents.

This disorder is a major limitation in the application of percutaneous vascular revascularization in patients with acute coronary syndrome, which is responsible for about 40% of postoperative disorders (Holmes et al., 1984).

Therefore, since the proliferation phenomenon occurs at a critical time corresponding to the first week after angioplasty, it is of primary importance in the preparation of available materials capable of inhibiting the proliferation of smooth muscle cells in the vessel wall after primary angioplasty for the prevention of stenosis. It is a goal.

Inhibition of proliferation in experimental atherosclerotic lesions may be indicated by cytostatic drugs such as etoposide (Llera-Moya et al., 1992), steroid hormones (Cavallero et al .; 1971; 1973; 1975; 1976). , Progesterone hormone (Spagnoli et al., 1990), dexamethasone (Asai et al., 1993).

Smooth muscle cell proliferation also affects both the reduction of DNA synthesis as in the case of verapamil (Stein et al., 1987) and the disruption of the second messenger system (cAMP) as demonstrated for nifedipine (Cheung et al., 1987). It is inhibited by calcium antagonists caused.

Treatment with ACE-inhibitors inhibited the growth of endovascular thickening (Powell, 1989).

Other in vitro studies have demonstrated a proliferation inhibitory effect on cultured smooth muscle cells of a given rat aorta by the HMG-CoA reductase inhibitor simvastatin used as a treatment for hyperlipidemia (Corsini et al., 1991). Moreover, some substances with triglyceride hypoglycemic effects, such as fibrate, have been shown to prevent the progression of atherosclerotic lesions in humans (Olsson et al., 1990).

In a manner similar to that observed in tumors (Kerr, 1994), it has been observed that population reduction in atherosclerotic populations and / or endovascular thickening occurs with cell proliferation (Gabbiani, 1995); It is helpful for extinction and suggests that its regulation plays an important role in the development of atherosclerosis.

Apoptosis has been demonstrated in various forms of human and experimental cardiovascular disease (Sharifi AM, Schriffin EL; Am. J. Hypertens. September 1998; 11 (9): 1108-16).

Angioplasty generates reactions in a number of vessel walls, including cell migration, proliferation, and interstitial accumulation, all of which contribute to neovascularization and stenosis (Malik N et al; Circulation 20 October 1998). 98 (16): 1657-65). Induction of apoptosis may also be beneficial in reversing vascular diseases such as pulmonary vascular disease (Cowan K. N. et al., Circ. Res. May 28, 1999; 84 (10): 1223-33). Stenosis after angioplasty is due to damaged endovascular cells.

The use of apoptotic agents, for example in the treatment of tumors, carries the risk of causing a generalized phenomenon with possible side effects, which can be very serious as in the case of hepatocytes.

There is a need to find whole cell killer without generalization.

Suggestions for preventing stenosis can be found, for example, in US Pat. Nos. 5,116,864 and 5,835,935.

U. S. Patent No. 5,786, 326 considers the phenomenon of stenosis and indicates that iron is an important requirement for the proliferation of SMC. The techniques discussed in this patent teach drugs that act as iron chelating agents as a means of preventing stenosis. U. S. Patent No. 5,786, 326 provides a new iron chelating agent, ie exokelin.

Apoptosis in Tumors

It is well known that the use of anticancer agents in the treatment of humans causes a number of toxic effects or side effects that may be life threatening to the patient. Indeed, these complications reduce the dose of the anticancer agent, sometimes causing the treatment to stop.

In many cases, such dose reduction or discontinuation of treatment is beneficial for the recurrence of the disease and therefore worsens the general condition of the individual, which is sometimes fatal to the patient.

As the number and importance of anticancer agents used in the treatment of humans increases, their main limitations lead to the occurrence of toxic effects or side effects, which means that the problem is still of considerable concern.

Thus, there is a much greater need to find new agents or combinations of new and suitable different agents that can substantially reduce the toxic effects or side effects caused by anticancer agents used in human treatment.

One of the common problems of pharmacological therapy is the ratio of therapeutically effective doses of the medicament to the therapeutic index, ie the toxic dose or the dose that would cause the side effect anyway.

The medical community still recognizes the need for a treatment regimen that enables patients to face treatments that are particularly unbearable in chemotherapy, while maintaining an acceptable quality of life. This consideration also applies to the treatment of animals, for example pets.

The natural tendency to reduce the dosage, and therefore the use of pharmaceutical forms suitable for therapeutically useful administration without inevitably taking the anticancer agent too often, is contrary to the minimum effective dose typical for each anticancer agent.

Thus, materials that can interfere with tumor cells and exert the effects of anti-tumor drugs, such as those that induce apoptosis in tumor cells, even without true cytotoxic activity, will be very advantageous.

WO 97/34596 discloses the use of alkanoyl L-carnitine in the treatment of glutamate mediated diseases including cancer.

It has now been found that propionyl L-carnitine confers a specific inhibitory action on smooth muscle cells and tumor cells of blood vessels due to its unexpected procytotoxic effect.

Summary of the Invention

It is an object of the present invention, in particular, to produce propionyl L-carnitine for the preparation of a medicament useful for the treatment of pathologies which benefit from the induction of apoptosis in blood vessels, for example, stenosis after angioplasty or after coronary artery stenting, or especially tumors. And pharmacologically acceptable salts thereof.

The most important and surprising advantage of the present invention is that administration of propionyl L-carnitine does not involve toxic effects in the bone marrow and intestine, which have good production of blood cell elements and very good replacement of intestinal mucosa cells, respectively. These and other aspects of the invention will also be illustrated in detail by way of examples.

Propionyl L-carnitine has been disclosed as preventing the progression of atherosclerotic lesions in old hyperlipidemic rats (Spagnoli LG, Orlandi A., Marino B., Mauriello A., De Angelis C., Ramacci MT, Atherosclerosis 1995; 114; , 29-44). In this study, the authors demonstrate the potent atherosclerosis inhibitory effects of propionyl L-carnitine (also named PLC). This effect has been demonstrated in rabbits that are not clearly models applicable to humans, but have been found through lipid lowering effects. Indeed, the author said, “[...] the number of animals is not very large, but is sufficient to demonstrate a very significant reduction in total triglycerides, IDL- and VLDL-triglycerides [...], while plasma cholesterol levels are slightly Temporarily changed ”(p. 40, left column, lines 16-19). The authors also observed lower levels of proliferative activity in both macrophages and the SMC constituting plaques (same document, last 5 lines). The author then stated, "at present, we cannot estimate what therapeutic use the PLC has" (same document, right column, first 3 lines). However, the results of this study established the atherosgenic role of β-VLDL in the progression and / or conversion of age-related endometrial thickening of fibrous atherosclerotic plaques (same literature, lines 5-10). The authors hypothesize that plasma triglyceride levels are directly related to the proliferative activity of plaque cell populations and that pharmacological regulation of these two factors may be associated with a marked reduction in plaque progression in older hypercholesterolemia rabbits. In addition, some experimental data support the hypothesis about the correlation between triglycerides and cell proliferation (e.g., p. 41, right column, lines 20-29). The authors said, “PLC does not seem to act through the regulation of the expression of [...] growth factors (same document, last two lines), and whether or not PLC directly inhibits cell proliferation of atherosclerotic plaques, Further ex vivo studies are needed to answer the question ”(same literature, p. 42, final line).

The teaching of the study is that PLC prevents the progression of atherosclerotic lesions in older hyperlipidemic rabbits as a treatment for hyperlipidemia. Thus, in the drop of lipids that contribute to cell proliferation of atherosclerotic plaques, PLC acts indirectly as an atherosclerosis inhibitor. Proliferation inhibitory action has not been demonstrated for PLC.

In subsequent studies (hypertension, Vol 28, No 2, August 1996, p. 177-182), some of the preceding authors examined the effect of PLC on diploid cells. "The ploidy seems to be associated with the disorder of SMC mitotic cleavage after DNA content doubling". According to the authors, PLC has been found to reduce the number of diploid cells but is ineffective in controlling blood pressure in SHR. They also teach that drained SMC causes hypertension, and the pathophysiological significance of drained SMC in the SHR aorta is unknown. The cell cycle blockade is then described. The hypothesis or mechanism exerted by the PLC does not suggest that the compound may have a total cell death action.

The present invention particularly propionyl L-carnitine for the preparation of a medicament useful for the treatment of pathologies which benefit from the induction of apoptosis of blood vessels, for example, stenosis or tumors after angioplasty or coronary stenting and pharmaceutically It relates to the use of acceptable salts.

The present invention is based on the application of the discovery that propionyl L-carnitine (hereinafter simply referred to as PLC) causes programmed death (cell death) in cells. This effect treats vascular pathologies based on the proliferation of smooth muscle cells in the vascular wall, such as stenosis after pulmonary hypertension, hypertension, angioplasty or coronary artery stenting.

Advantageously, PLC is a well known drug with quite limited side effects. Examples of propionyl l-carnitine are disclosed in US Pat. Nos. 44,15589 and 4255449, Italian Patent 1155772, EP 0793962 and 0811376, WO 99/17623, PCT / IT97 / 00113.

Thus, the first aspect of the present invention provides a prophylaxis for the preparation of a medicament useful for the treatment of pathologies, in particular stenosis after angioplasty or after coronary stenting, or in particular tumors, which have a therapeutic benefit from inducing apoptosis in blood vessels. Oyl L-carnitine and its pharmacologically acceptable salts.

Another object of the present invention is the use of propionyl L-carnitine and its pharmacologically acceptable salts for the manufacture of a medicament useful for the treatment of hypertension.

Another object of the present invention is the use of propionyl L-carnitine and its pharmacologically acceptable salts for the manufacture of a medicament useful for the treatment of pulmonary hypertension.

Still another object of the present invention is the use of propionyl L-carnitine and its pharmacologically acceptable salts for the manufacture of a medicament useful for the prevention of stenosis after angioplasty or coronary stenting.

The object of the invention disclosed herein is also the integrated use of propionyl L-carnitine according to the adjuvant effect obtained by an anticancer agent. As an adjuvant effect, the objective is that the PLC exerts an apoptotic effect on tumor cells by a combination therapy of anti-tumor drug and propionyl L-carnitine, and thus the PLC supports the apoptotic effect of the anti-tumor drug. In this way an improvement in the therapeutic index of antitumor drugs is expected.

A further object of the invention disclosed herein is the use of propionyl L-carnitine in the manufacture of a medicament useful for the treatment of tumors.

Still another object of the present invention disclosed herein is the combination of propionyl L-carnitine with an anticancer agent and related pharmaceutical composition.

In connection with the invention disclosed herein, the "integrated use" of the compounds means, without distinction, (i) co-administration of an anticancer agent with one of propionyl L-carnitine or one of its pharmacologically acceptable salts, or ( ii) administration of a composition comprising said active ingredients together in a mixture, in addition to any pharmaceutically acceptable excipients and / or vehicles.

Accordingly, the invention disclosed herein includes both co-administration of an anticancer agent with one of propionyl L-carnitine or its pharmacologically acceptable salts, and a pharmaceutical composition, wherein these are controlled releases comprising the two active ingredients in a mixture It may be administered orally, parenterally or intranasally, including in a given form.

Although apparent from the detailed description below, the present invention may also contemplate the integrated use of anticancer agents such as Taxol, Bleomycin, Carboplatin, Vincristine, Camptothecin. In all such embodiments, propionyl L-carnitine can be used in integrated applications.

Co-administration also includes propionyl L-carnitine or one of its pharmacologically acceptable salts in separate dosage forms and an anticancer agent and incorporates the active ingredients according to the administration regimen specified by the attending physician based on the condition of the patient. Means a package or product with a simultaneous or time-specified dosing guide.

Embodiments of the invention disclosed herein also heal a patient due to increased therapeutic success due to the possibility of increasing the dose of chemotherapeutic agent or maintaining the intended treatment protocol without interrupting treatment due to contraindications. Contributes to prolonging his life. In addition, the adjuvant effect of propionyl L-carnitine may predict a dose reduction of anticancer drugs.

In accordance with the present invention, a medicament according to the present invention may be considered for the administration of the active ingredient (propionyl L-carnitine or a pharmacologically acceptable salt thereof) in the gut (particularly oral) or parenteral (particularly via the intramuscular or intravenous route) It can be obtained by mixing with excipients suitable for the formulation of the composition. All such excipients are well known to those skilled in the art.

As pharmaceutically acceptable salts of propionyl L-carnitine, any salt with an acid that does not produce unwanted side effects is contemplated. Such acids are well known to pharmacologists and pharmaceutical technical experts.

Non-limiting examples of such salts are chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, lactate, maleate and acid maleate, acid oxalate, acid sulfate, glucose phosphate , Tartrate and acid tartrate.

Some examples of single dosage form formulations are as follows.

(a) tablet formulation

(b) Intravenous Injectable Bottle Container Formulation

A medicament prepared according to the present invention will be administered in the form of a pharmaceutical composition which may be prepared according to the general common knowledge of those skilled in the art.

Depending on the route of administration, oral, parenteral or intravenous route suitably selected, the pharmaceutical composition will be in a suitable form.

Examples of pharmaceutical compositions comprising a medicament according to the invention are solid or liquid oral forms, e.g. tablets, capsules, pills, solutions, suspensions of all types, emulsions, syrups, single or divided dose forms, ready to use or ready to use There is a unit dosage form available for drinking. Other examples are parenteral forms, injectable forms for intramuscular, subcutaneous or intravenous administration. Modified or programmed releases are also suitable.

Dosage, dosage, and general treatment regimen will be determined by the physician according to the physician's knowledge, the patient's condition, and the pathology to be treated.

Association of the PLC with other active ingredients, whether co-administered with the same medicament or separately (simultaneously or subsequently), is also included in the present invention.

In a first preferred embodiment, the invention relates to stenosis after angioplasty.

According to this first preferred embodiment, the pharmacological dose of PLC does not exceed a blood concentration of 100 mM.

The following examples further illustrate the invention.

Example 1

Wistar male rats weighing 270-290 mg were used for the experiment. The rats were intraperitoneally anesthetized with nembutal (35 mg / kg body weight) and slightly modified from the thoracic part of the aorta (Orlandi 1994) according to the method of Baugartner and Studer (1996) Fogarty. Endothelial was mechanically removed by 2F balloon probe (Baxter USA). The animals were randomized into five groups and each group is recorded in Table 1.

Two groups were pharmacologically treated with propionyl L-carnitine (PLC, 120 mg / kg, pc death) and one group was treated with ACE-inhibitor (enalapril, 1 mg / kg, pc death) ; The other two groups were controls. Furthermore, some of the untreated animals were blanked.

Animals were killed 3 and 15 days after endothelial removal. Two hours prior to killing, all rats received intravenous bromodeoxyuridine solution (BrDU) (45 mg / kg) to confirm cell proliferation. One hour before killing, some randomly selected animals received 1 ml of Blue Evans (1% in 0.9% NaCl solution) to assess the degree of aortic rupture.

Upon killing, animals were anesthetized intraperitoneally with nembutal, washed with isotonic saline containing 3% dextran 70 and then perfused with buffered formalin for 20 minutes. Arteries were isolated, washed lightly with saline and incised longitudinally. The carotid artery, heart and small intestine were also excised. The organs were all post-fixed with the same fixer at room temperature for 24 hours.

Some aortic fragments were used for electron microscopy. The aorta was rolled up and placed in paraffin. A series of 5 μm thick cross sections were stained with hematoxylin-eosin, verhoef-van Gison, and Pentachrome from Mobat and used for morphological and morphometric studies.

In some non-perfusion animals, fragments of aortic tissue were frozen in liquid nitrogen for measurement of tissue carnitine and subsequent molecular biology studies.

Immunohistochemical Staining

To explain the pronounced cell proliferation of the damaged artery, paraffin was removed from a series of aortic sections in paraffin, rehydrated, soaked in 3% H ₂ O ₂ solution for 20 minutes and trypsin (0.05 in Tris-HCl). M, pH 7.6). Thereafter, the portions were treated with 2N HCl for 30 minutes at 37 ° C., washed with 0.1 M sodium tetraborate and incubated for 1 hour with normal horse serum (Vector) and subsequently anti-BrDU monoclonal antibody (Ylem). It was. The preparation was then reacted with biotilinated anti-mouse IgG (Vector) and streptoavidin-ABC-POD complex (Ylem).

The reaction was demonstrated using diaminobenzidine (DAB) as the final color source. The number of positive nuclei for BrDU was counted against the total number of nuclei. This count was performed by two researchers on a separate blinded basis. The difference between the two counts was always less than 0.5%.

All data were analyzed by the T Student test. Differences between the groups were considered as significance levels for P <0.05.

Morphometric Analysis

The presence of vascular endometrial thickening after 15 days was assessed for the Verhoef-Bangsonon stained portions using a grid (consisting of 400 points) superimposed on the phase 1 cm from each other.

The analysis was performed on histological preparations via a Hamamatsu C3077 camera controlled by a Hamamatsu DVS 3000 phase analyzer and connected to a Polyvar-Reichert microscope. Morphometric evaluation was performed at X116 magnification. A) the relative volume of the vascular lining belonging to the arterial wall by counting the overlapping points on the vascular lining and normal film; b) Relative volume of media in the artery wall was evaluated.

Three to twelve aortic sections were used at different levels for each animal. The number was a function of the size of the structure according to the Sach's formula indicating the number of fields needed to obtain a statistically significant sample.

Ultrastructural Research

Small aortic samples were selected for electron microscopic analysis. The aorta was post-settled in osmium tetraoxide and embedded in EPON 812. Ultra-thin portions were stained with uranil acetate followed by lead citrate and examined using a Hitachi H-7100 FA transmission electron microscope.

Tissue and Plasma Carnitine Analysis

2-3 ml of blood samples were collected from each animal before mechanically removing the endothelium and upon killing. Plasma was separated by 20 minutes centrifugation (300 rpm) and frozen for analysis of plasma carnitine according to the method of Pace et al.

Aortic wall samples were recovered from some non-perfusion animals randomly selected from each group, frozen in liquid nitrogen and stored at −80 ° C. for analysis of carnitine according to the literature, such as Pace et al.

result

Ultrastructural Research

Small aortic samples were selected for electron microscopy analysis. The aorta was post-fixed in osmium tetraoxide and buried in EPOC 812. Ultra thin sections were stained with uranil acetate followed by lead citrate and examined using a Hitachi H-7100 FA transmission electron microscope.

Tissue and Plasma Carnitine Analysis

2-3 ml of blood samples were withdrawn from each animal before mechanically removing the endothelium and immediately before killing. Plasma was separated by 20 minutes centrifugation (3000 rpm) and frozen for analysis of plasma carnitine according to methods such as pace.

Aortic wall samples were recovered from some non-perfusion animals randomly selected from each group, frozen in liquid nitrogen and stored at −80 ° C. for analysis of carnitine according to the literature, such as Pace et al.

result

Damage mode

After 3 days of mechanical injury, the rat aorta showed no significant histological changes except for the lack of endothelial cell coat.

After 15 days, remodeling of the arteries could be observed by the presence of vascular endometrial thickening (or neovascularization) present as rounded or elongated cells submerged in abundant extracellular cytoplasm. Immunohistochemical studies clearly demonstrate the presence of abundant smooth muscle (SMC), especially inside the neointima.

Proliferation

a) Day 3 after endothelial removal: The count of anti-BrDU staining positive nuclei showed significant difference between the two groups examined. Quantitative analysis (Table 2) clearly demonstrates that the number of BrDU-positive nuclei is significantly lower in the media of PLC-treated animals relative to the control (59.3% reduction for control, p <0.02). In both groups, the distribution of BrDU-positive nuclei is more concentrated in the ratio of 2: 1 to the lumen portion of the membrane, usually relative to the outer membrane portion.

b) 15 days after endothelial removal: Table 3 shows that the proliferation index of SMC in each group was significantly higher (p <0.001) in the intima versus intima. No significant difference in the number of BrDU-positive nuclei in the intima and intima was observed by comparison of PLC, enalapril and control animals.

Morphometric Analysis

As shown in Table 3, after 15 days from endothelial injury, the relative volume of the endometrium was reduced in PLC-treated animals (31.11% reduction for control, p <0.02) and ACE antagonist-treated animals (control) compared to control animals. 26.14% decrease, p <0.01), which is significantly lower in all cases.

Effect of propionyl L-carnitine on the regulation of proliferation / apoptosis

Experiment to evaluate the effect of propionyl L-carnitine (PLC) on smooth muscle (SMC) isolated from aorta of rats (SHR) that are spontaneously hypertensive in vitro and SMC isolated from rats of normal blood pressure (WKY) as a control Was performed.

This in vitro study demonstrated that PLC reduced DNA synthesis assessed through binding of tritiated thymidine as well as cell growth assessed as cell number / ml when administered during the culture index propagation phase (Tables 4 and 5). .

As a further feature of smooth muscle cells in the presence of PLC, the percentage of apoptotic cells was measured in both basic and oxidative stress conditions. Apoptosis was assessed by counting the number of apoptotic cells present on a total of 1000 cells after staining specific DNA with Hoechst 33258. The results of the experiment demonstrated that PLC significantly increased the percentage of apoptosis in the basic state in SHR culture, and this increase was more pronounced under stress state.

In WKY culture, the percentage of apoptosis is negligible (Table 6).

Aspects observed in SHR smooth muscle cells may be somehow related to the deregulated expression of c-myc characterizing autologous hypertensive rats (Negoro et al., 1988). Moreover, it has been observed that c-myc actively cooperates in inducing apoptosis following proliferation disruption (Bennet et al., 1993; Bissonette et al., 1993), thus the data presented above shows that the PLC proliferation inhibitory effect is due to DNA. It may be related to disrupting replication.

Example 2

Cell line

Tumor cells of human origin obtained from Istituto Zooprofilattico of Brescia were cultured. The cells used in the experiment were U266, multiple myeloma, HeLa, cervical tumor, K562, chronic myeloid leukocytes. HeLa and K562 were cultured in RPMI + 10% FCS, while U266 cell line was cultured in RPMI + 15% FCS, both of which contained penicillin / streptomycin (50 U / ml and 50 μg / ml). Cells were plated in 6-well plates (Falcon). 50% fused cells were analyzed.

Each cell line was treated with PCL according to the following scheme:

a) for 24 hours with 1 mM PLC (Figures 1-3);

For 48 hours with 1 mM PLC (Figures 1-3);

b) 24 hours with 1 mM PLC followed by 24 hours with medium without molecules (Figures 4-6).

At the end of each treatment, cells were counted in a Burker chamber in the presence of trypan blue 0.5% diluted 1: 2. Samples from three wells were counted for each experimental group.

Treatment of tumor cell lines of human origin with 1 mM propionyl L-carnitine shows the ability to inhibit proliferation both after 24 hours and after 48 hours. In particular for HeLa, the inhibition rates after 24 and 48 hours for the control group were 25% and 17%, respectively; For U266, 46% and 26% after 24 and 48 hours for the control group; K562 was 37% and 39% after 24 and 48 hours for the control.

The PLC inhibitory effect persists even after removing the material from the culture medium. Indeed, in this case the cells were treated with 1 nM PLC for 24 hours, then the PLC containing medium was removed and fresh medium added without this material. Inhibition values were 20%, 26% and 21% for HeLa, U266 and K562, respectively.

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Claims (9)

Use of propionyl L-carnitine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of a pathology that would benefit from induction of apoptosis. Use according to claim 1, wherein the medicament is useful for the treatment of hypertension. Use according to claim 1, wherein the medicament is useful for the treatment of pulmonary hypertension. Use according to claim 1, wherein the medicament is useful for the prevention of stenosis after angioplasty or coronary stenting. The use of claim 1, wherein the medicament is useful for the treatment of a tumor. 6. The salt according to claim 1, wherein the salt of propionyl L-carnitine is selected from chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, lactate, Uses selected from the group consisting of maleate and acid maleate, acid oxalate, acid sulfate, glucose phosphate, tartrate and acid tartrate. A combination drug comprising an antitumor drug and propionyl L-carnitine, provided the antitumor drug is not doxorubicin. Use of the combination drug according to claim 7 for the manufacture of a medicament with anticancer activity, characterized in that the medicament comprises an effective amount of propionyl L-carnitine that exerts an adjuvant action against anticancer activity. A package or product comprising propionyl L-carnitine or one of its pharmacologically acceptable salts in a separate dosage form, and an anticancer agent excluding doxorubicin, to which an integrated simultaneous or timed dosing of the active ingredients is attached.