MXPA01001065A - Use of l-carnitine and its alkanoyl derivatives in the preparation of medicaments with anticancer activity - Google Patents

Abstract

The invention described herein relates to the use of alkanoyl L-carnitine with formula (I) where R and X- are as defined in the description, in the preparation of medicaments useful for the treatment of tumours;in particular, the invention described herein refers to combinations of alkanoyl L-carnitine and anticancer agents for the treatment of tumours with an improvement in the therapeutic index and a reduction of the side effects typical of anticancer chemotherapy.

Description

USE OF L-CARNITINE AND ITS ALCANOILO DERIVATIVES IN THE PREPARATION OF MEDICINES WITH ACTIVITY AGAINST CANCER FIELD OF THE INVENTION The present invention relates to the use of L-carnitine and alkanoyl-L-carnitines in the preparation of medicaments useful in the treatment of tumors, particularly in combination with anticancer agents, for the treatment of tumors. BACKGROUND OF THE INVENTION It is well known that the use of anti-cancer agents in human therapy causes a large number of toxic or secondary effects that can threaten the lives of patients. These complications, in fact, can cause a reduction in the doses of the agents and occasionally discontinue the therapy itself. The reduction of the dose or the discontinuity of the therapy in many cases causes a deterioration of the general condition of the individual, because it favors the development of relapses, with consequences that are sometimes fatal for the patient. Another very important aspect that is very important in the hospital and among the relatives of cancer patients is the concept of "improving the quality of life" of patients under treatment.

Ref: 126823 It is also known that patients who undergo regular polychemotherapy for cancer are subject to a substantial weight loss. The increasing number and importance of anti-cancer agents used in human therapy, whose main limitation continues to be the presence of toxic or secondary effects, means that this problem is still a matter of considerable concern. Thus, the discovery of new agents or new appropriate combinations of different agents capable of substantially reducing the toxic or secondary effects caused by the anti-cancer agents used in. human therapy, it is very desirable. The previous uses of L-carnitine in combination with anti-cancer agents are already known. In experimental animal models, it has been shown that rats treated with doxorubicin alone show greater weight loss than a group of rats treated with the same substance in combination with L-carnitine (Seneko itsch R, Lohninger A, Kriegel H., Stanik H., Krieglsteiner HP., Kaiser E. Protective effects of carnitine on adriamycin toxicity to heart In: Kaiser E., Lohninger A., (eds.) Carnitine: its role in lung and heart disorders: 126-137. , Basel-Ne York, 1987).

U.S. Patent No. 4,713,370 describes the use of carnitine in combination with cytostatic agents such as daunomycin, N-acetyldaunomycin and daunomycin oxime, to reduce the cardiac toxicity of these compounds. US Pat. No. 4,267,163 discloses the use of carnitine in combination with cytostatic agents such as adriamycin, adriamycin-14-octanoate, 4 '-epi-adria icine, beta-anomer of adriamycin and gamma-anomer of the -epi-adriamycin to reduce the cardiac toxicity of these compounds. U.S. Patent No. 4,751,242 describes the use of acetyl-L-carnitine for the therapeutic treatment of peripheral neuropathies. Other studies have addressed the evaluation of the protective effects of carnitines on cardiac toxicity induced by anthracycline (Neri B., Comparini T., Milani a, Torcia M., Clin.P Trial J. 20, 98-103, 1983; De Leonardis V., De Scalzi M., Neri B., et al. , Int. J. Clin. Pharm. Res. 70, 307-311, 1987). The aforementioned patents and references demonstrate that numerous efforts have been made in an attempt to reduce the toxic or secondary effects of the anticancer agents, but without satisfactorily solving this serious problem.

Carboplatin is a structural analogue of cisplatin and is associated with nephrotoxicity, although by no means negligible, it is less than that of cisplatin. Vincristine is a well-known cancer agent that has toxic effects, particularly at the level of the immune system. Taxol is a natural extract, isolated for the first time from the bark of Taxus brevifolia, with anti-cancer properties and has been proven to have neurotoxic and myelotoxic effects in humans. It is used for the treatment of tumors resistant to platinum therapy, but it gives rise to a greater cumulative toxicity in the peripheral nervous system. It has also been argued that taxol induces neutropenia in treated subjects (Rowinsky et al., Semin. Oncol. (1993, August 20 (4 suppl 3), 1-15).; Onetto et al. , J. Nati. Cancer Inst. Monogr. (1993); (15): 131-9). Bleomycin is typically used in young patients with testicular cancer, lymphoma and other types of tumors. The pulmonary toxicity of bleomycin is characterized by the destruction of the alveolar epithelial barrier and the consequent intraalveolar proliferation of fibroblasts and the deposition of extracellular matrix components (Kara H et al., Cell Biol. Toxicol (1998 Feb); 14 ( 1): 13-22). Type 2 pneumocytes are not able to regenerate damaged or lost epithelium. One of the general problems of pharmacological therapy is the therapeutic index of the agents; that is, the ratio of the therapeutically effective dose to the toxic dose or, at any ratio, the dose that gives rise to the emergence of side effects. The medical community still perceives the need for therapeutic regimens that allow the patient to face the treatment, which, in the case of cancer chemotherapy, is particularly difficult to support, while at the same time maintaining an acceptable quality of life. These considerations also apply to the therapeutic treatment of animals, for example pets. The natural tendency to reduce the doses and therefore the use of suitable dosage forms for therapeutically useful administrations without forcing the patient to take the agents too regularly, contrasts with the minimum effective doses typical of each agent against cancer. BRIEF DESCRIPTION OF THE INVENTION Surprisingly, it has been found that the coordinated use - this term will be defined more precisely below - of an anti-cancer agent and an L-carnitine or an alkanoyl-L-carnitine, as will be defined below. , exerts an unexpected synergistic effect on the activity of the agent against cancer. In the context of the present disclosure, it has also unexpectedly been found that the coordinated use of a therapeutically effective amount of an anti-cancer agent, in particular taxol, carboplatin, bleomycin and vincristine, with a detoxifying amount of L- carnitine or an alkanoyl-L-carnitine, where the alkanoyl group is straight or branched chain and has 2 to 8 carbon atoms, or one of its pharmacologically acceptable salts, achieves a potent protective effect against toxicity and side effects of the agent against cancer, without detracting from its efficacy, thus giving rise, among other things, to a substantial improvement in the quality of life and in the prolongation of the life itself of the treated subjects, whether human or animal subjects. It has also been found that such coordinated use has an inhibitory effect on tumor metastasis. Therefore, an object of the present invention is the use of a compound of the formula (I): wherein R is hydrogen or an alkanoyl group of 2 to 8 carbon atoms and X- represents the anion of a pharmaceutically acceptable salt , for the preparation of a medicament comprising a people against cancer, characterized in that the compound produces a synergistic effect on the activity of the agent against cancer. Also an object of the present invention is the coordinated use of a compound of the formula (I) according to which the side effects of the anti-cancer agent of said medicament are substantially reduced. Another object of the present invention is the use of a compound of the formula (I) in the preparation of a medicament useful for inhibiting metastasis. Still another object of the present invention are combinations of the compound of the formula (I) with anticancer agents and the related pharmaceutical compositions. The known lack of toxicity or side effects of alkanoyl-L-carnitines, makes the use of these compounds particularly safe for prolonged periods of treatment, for the prevention or treatment of toxic or secondary effects, such as weight loss , effects on the heart, kidneys and central nervous system, damage to the peripheral nervous system, neuropathy or neutropenia particularly caused by taxol, or pulmonary damage induced by bleomycin. The implantation of the present invention also contributes to improving the quality of life of the treated patients; one only needs to think about the physical suffering caused by peripheral neuropathy, neutropenia, respiratory complications or impairment due to weight loss caused by these agents. These and other objects of the present invention will be described in greater detail in the preferred embodiments of the present invention, and also by way of examples. In the context of the present invention, the terms "antineoplastic", "against cancer" and "antiproliferative" should be understood to be essentially synonymous. DETAILED DESCRIPTION OF THE INVENTION In the context of the present invention, the term "coordinated use" of the aforementioned compounds, is either (i) coadministered, i.e. the substantially simultaneous administration or sequential administration of L-carnitine or an alkanoyl-L-carnitine or one of its pharmacologically acceptable salts and an anti-cancer agent, or (ii) the administration of a composition comprising the aforementioned active ingredients. in combination and in a mixture, in addition to the optional pharmaceutically acceptable excipients and / or vehicles. The present invention, therefore, covers both the coadministration of L-carnitine or an alkanoyl-L-carnitine or a pharmacologically acceptable salt thereof of formula (I) and an anticancer agent, and pharmaceutical compositions which can be administered orally, parenterally or nasally, including controlled release forms, which comprise the active ingredients in a mixture. Preferably, the alkanoyl L-carnitine is selected from the group consisting of acetyl-L-carnitine (hereinafter abbreviated as ALC or Alear), propionyl-L-carnitine (hereinafter abbreviated as PLC), butyryl- L-carnitine, valeryl-L-carnitine and isovaleryl-L-carnitine, or one of its pharmacologically acceptable salts. The preferred substances are acetyl-L-carnitine, propionyl-L-carnitine and butyryl-L-carnitine.

Although it will be clear from the following detailed description of the invention, it is also possible to provide for the coordinated use of an anticancer agent, such as taxol, acetyl-L-carnitine and propionyl-L-carnitine, or the use of bleomycin and acetyl-L-carnitine, or -other possibility- the use of acetyl-L-carnitine and taxol or carboplatin or vincristine. In all these modalities, L-carnitine can be used in a coordinated manner. Co-administration also means a package or article of manufacture comprising the administration of different forms of L-carnitine or one of the aforementioned alkanoyl-L-carnitines, or one of its pharmacologically acceptable salts and an anti-cancer agent, accompanied by instructions for the simultaneous coordinated or scheduled administration of the active ingredients in accordance with a dose regime established by the primary care physician, based on the patient's condition. The term "pharmacologically acceptable salt" of L-carnitine or of an alkanoyl-L-carnitine, means any salt of the latter prepared with an acid that does not produce toxic or secondary effects. These acids are known to pharmacologists and experts in pharmaceutical technology.

Examples of pharmacologically acceptable salts of L-carnitine or of the alkanoyl-L-carnitines, although not exclusively these, are the chloride, bromide, iodide salts; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate; acid phosphate; fumarate; acid fumarate, glycerophosphate, glucose phosphate, lactate, maleate, acid maleate, mucate, orotate, oxalate, oxalate acid, sulfate, acid sulfate, trichloroacetate, trifluoroacetate, methanesulfonate, pamoate and pamoate acid. A preferred form of daily dose of L-carnitine or alkanoyl-L-carnitine for clinical use, is a composition comprising an amount of L-carnitine or an alkanoyl-L-carnitine, preferably acetyl or propionyl-L-carnitine, equivalent at 0.1 to 3 g, and preferably 0.5 to 3 g. The present invention is advantageous in the prevention or treatment of toxic or secondary effects such as weight loss, damage to the heart, kidneys and central nervous system, damage to the peripheral nervous system, peripheral neuropathy and particularly the myelosuppression and lung damage caused by the aforementioned anti-cancer agents. The term "substantially protective effect" as used herein means the prevention, reduction or elimination of the side effect to a statistically significant degree. The embodiment of the present invention that is described here also contributes to healing and prolonging the life of patients thanks to the increase in therapeutic success due to the possibility of maintaining the programmed treatment protocols or the increase of the doses of the chemotherapeutic agent, without having to discontinue treatment because of contraindications. Another benefit obtained with the present invention is related to the quality of life of the subjects treated; in fact, as already mentioned, the elimination or reduction of physical suffering caused by a peripheral neuropathy or by the debilitation caused by weight loss, favors the ability of patients to be self-sufficient. From the economic point of view, there are obvious savings in terms of the costs incurred by hospitalization or by the family for patient care. Myelosuppression is one of the side effects that can be manifested as a result of the administration of taxol, which is a chemotherapeutic agent used in the therapy of various tumors, for example breast tumors, ovaries, lungs (small cell and others), of head and neck (Slichenmeyer and Von Hoff: J. Clin. Pharmacol. (1990), 30, 770-778).

The vehicle adopted for taxol also in commercial pharmaceutical forms (TAXOL, Bristol Myers Squibb), is a derivative of polyethoxylated castor oil, known commercially as ® Cremophor EL and is capable of inducing the release of histamine and causing reactions. anaphylactoids in dogs and humans (Slichenmeyer and Von Hoff: ibid.); Bury et al. : Allergy (1992), 47, 624-629; Hershkoviz et al. : J. Leukoc. Biol. (1994), 56, 495-501; Inokuma et al. : J. Vet. Med. Sci. (1994), 56, 45-49). In view of the fact that the drug marketed has Cremophor® EL as vehicle, the problem of myelotoxicity related to the preparation used in therapy has been abated. One of the most serious problems encountered in the course of proliferative diseases is the metastatic spread of the tumor, which sometimes progresses to such an extent that the treatment of the primary tumor becomes useless and by itself becomes the cause of death. In a first preferred embodiment of the present invention, L-carnitine, combined with an anti-cancer agent such as taxol, carboplatin or vincristine, ensures the extension of the survival of the treated subject. In a second embodiment of the present invention, acetyl-L-carnitine has shown an unexpected degree of protective activity against side effects induced by taxol, such as peripheral neuropathy, myelosuppression and weight loss. In a third embodiment of the present invention, it has been shown that acetyl-L-carnitine suppresses the antimetastatic activity when administered concomitantly with taxol, particularly in lung cancer. In accordance with another preferred embodiment of the present invention, propionyl-L-carnitine has demonstrated an unexpected synergistic effect in combination with taxol. It has been found that taxol induces severe neutropenia with a nadir after the third to fourth injection of the compound. When an ALC is used in accordance with the present invention, no adverse effects on the cancer action of the drug are found. The ALC can be administered, conveniently, orally without for that reason other routes of administration being excluded, which a person skilled in the art could consider advisable, particularly injections, to be administered concomitantly, for example, in the same line of administration. infusion, with the agent against cancer, or in sequence as established by a technician in the field. Likewise, propionyl-L-carnitine (PLC) has shown a synergistic effect with the therapeutic activity of taxol. Therefore, it is clearly advantageous to provide a ternary combination, also in separate pharmaceutical forms, or in combination, of acetyl-L-carnitine as a protective agent, propionyl-L-carnitine as a synergistic agent and taxol. This combination also comprises other anticancer agents that show a synergistic effect or induce substantially reduced side effects as a result of the combination in accordance with the present invention. It can also be advantageous to add L-carnitine to the aforementioned combination. A specific objective of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of taxol together with a protective amount of acetyl-L-carnitine and a synergistic amount of propionyl-L-carnitine, in a mixture with pharmaceutically acceptable carriers and / or excipients.

In a different embodiment, it is advantageous in any case to provide a binary combination of acetyl-L-carnitine as a protective agent and bleomycin. With reference to aspects related to industrial applicability, the present invention also provides, in one of its possible embodiments, a package containing a) a pharmaceutical composition comprising a therapeutically effective amount of an anti-cancer agent; b) a pharmaceutical composition comprising at least one alkanoyl-L-carnitine, as defined above, in an amount suitable to produce a synergistic effect with said agent against cancer; c) a pharmaceutical combination comprising at least one alkanoyl-L-carnitine and / or L-carnitine, as defined above, in a suitable amount to produce a substantially protective action against the side effects of the anticancer agent. The package according to the present invention may also be presented in the form of a) a pharmaceutical composition comprising a therapeutically effective amount of an anticancer agent; b) a pharmaceutical composition comprising at least one alkanoyl-L-carnitine in an amount suitable to produce a synergistic effect with said anti-cancer agent. Alternatively, the package according to the present invention may also be presented in the form of a) a pharmaceutical composition comprising a therapeutically effective amount of an anti-cancer agent; and b) a pharmaceutical composition comprising at least one alkanoyl-L-carnitine and / or L-carnitine in a suitable amount to produce a substantially protective action against the side effects of the anti-cancer agent. Specific examples of the aforementioned packages consider carboplatin, vincristine, taxol and bleomycin as the anticancer agent. Now, ways of implementing the present invention will be described with reference to the preferred embodiment, using taxol as the anti-cancer agent, acetyl-L-carnitine as the substantially protective agent and propionyl-L-carnitine as the substantially synergistic agent. It should be understood that a technician in the field could complete the experimental protocols with his general knowledge on the subject in which he works, possibly resorting to neighboring sectors if necessary. Below are reported the results of the most significant experiments suitable to demonstrate the unexpected and surprising protective effect obtained by the combination of L-carnitine or its derivatives with the aforementioned anticancer agents. EXAMPLE 1 Variations of survival time in rats treated with anticancer agents The purpose of this experiment is to demonstrate and evaluate the protective effect expressed as an increase in survival time, induced by L-carnitine in a murine experimental model. Groups of 10 male Wistar rats of 3 months of age (Charles River), housed at 22 ± 2 ° C with 50 ± 15% relative humidity and a light / dark cycle of 12 hours, fed with water and feed were used " ad libi tum. " The substances used were: L-carnitine, taxol, carboplatin and vincristine. The rats were treated with the anti-cancer agents intravenously (iv) at the doses corresponding to the respective DL30, LD50 and DL8o- The treatments with L-carnitine, 200 mg / kg, were administered subcutaneously once to the day, starting 8 days before the administration of the agent against cancer and continuing for another 14 days. The mortality of the rats, identified immediately before the treatment by means of progressive numbers in their tails, was supervised daily for 14 days after the administration of the agent against cancer; the experimental data were evaluated using the Wilcoxon and Log-Rango tests and the statistical significance test obtained in the evaluation of the experimental data, as reported in Table 1 below. TABLE 1 Evaluation of the survival time of rats treated with L-carnitine and an anti-cancer agent, at three different dose levels Significance refers to the combination versus the respective control (agent against cancer only at the same dose).

The results obtained that are presented in Table 1, show a significantly longer survival time in the groups treated with L-carnitine and the anticancer agent. The results of the statistical analyzes reported in Table 1 show two "p" values. The first was calculated using the Wilcoxon test; the second, i.e. the value "p" enclosed in parentheses, was calculated using the Log-Rank test. The discrepancies between the results of the two tests, Wilcoxon and Log-Rango, are due to the fact that the first is more powerful to detect differences in the first part of the survival curve and the last in the second part. . In the experiment performed, differences in survival times occur mainly in the first part of the curve. The lack of statistical significance in the comparisons between the low doses can be explained by the fact that, due to the low number of deaths, the tests are not very powerful to detect differences between the groups. EXAMPLE 2 Protective effect of acetyl-L-carnitine in an experimental model of peripheral neuropathy induced by taxol The purpose of this study is to determine and evaluate the protective properties of acetyl-L-carnitine administered one week before taxol, to two different dose of the latter &16 mg / kg and 8 mg / kg), measuring the speed of sensory nerve conduction (VCNS), determined in the tail and by means of the reflex H. Female Wistar rats of 3 months of age were used ( Charles River), housed at 22 ± 2 ° C, with 50 ± 15% relative humidity and a light / dark cycle of 12 hours. The rats were identified immediately before the treatment by means of progressive numbers in the tails and were fed with water and food "ad Ubi tum". The substances used were L-carnitine and taxol. The following experimental groups were formed: 1. Controls 2. Feigned (group that received a solution of taxol in a solvent). 3. Taxol, 16 mg / kg 4. Acetyl-L-carnitine + taxol, 16 mg / kg 5. Taxol, 8 mg / kg 6. Acetyl-L-carnitine + taxol, 8 mg / kg.

The following treatment program was used: the animals of the Fingido group received a solution of taxol in a solvent (cremophor / ethanol) intraperitoneally (i.p.); the taxol was administered i.p. once a week for 5 weeks; The treatments with L-carnitine, 200 mg / kg, were administered orally once a day through a gastric tube, starting one week before the first administration of taxol and continuing for another 4 weeks (5 weeks in total). The following method was used: the animals, anesthetized with a gaseous mixture composed of 0.45 parts of halothane, nitrous oxide and oxygen, were depilated in the stimulation zone and placed on a surgical table. The records and stimulations of the sensory responses were made using an Ote Biomedica Phasis II electromyograph. In view of the fact that scientific literature reports that the speed of nervous conduction depends on the body temperature of the animal, it was necessary to maintain the temperature constant during the experiment, measuring it with a rectal probe, with the help of a BM 70002 terptor regulator for animals.

(Biomedica Mangoni). The measurement of the conduction velocity of sensory fibers was obtained in the tail with a stimulation of steel ring type and measurement electrodes of 46 cm in length (Modelec digital ring electrodes), using a stimulation intensity equal to the threshold value with a duration of 100 microseconds. The average value of 300 responses was considered as potential. The sensory nerve conduction velocity, expressed in ms, was calculated as the ratio of the distance between the two stimulation points, expressed in mm, with respect to the difference in latency of the waves produced by proximal stimulation (the closest) and distal (the farthest from the spine), expressed in ms. Speed was measured in all groups of animals both at baseline (before any administration) and after 5 weeks of treatment. The results were expressed as the mean ± standard deviation; the significance was evaluated using the "t" test, both for independent data and for paired data, with a cut of statistical significance of p < 0.05. The sensory nerve conduction velocity data, measured in the caudal nerve, are presented in Table 2, which is presented below.

TABLE 2 Taxol-induced neuropathy: sensory nerve conduction velocity (m / s) measured in the tail of animals under basal conditions and after treatment with L-carnitine The values are the mean ± standard deviation. The number in parentheses is that of the animals used. Test t (independent data) ** = p < 0.01 vs CONTROL; A = P < 0.01 vs corresponding taxol. Test t (paired data)? = p < 0.01 basal.

Under basal conditions, all groups of animals showed well-matched nerve conduction values. The measurement at 5 weeks reveals a statistically significant increase (p <0.01) in the sensory nerve conduction velocity in all groups, compared to the baseline conditions. Treatment with taxol in a solvent (group Fingido) did not modify nerve conduction velocity values compared to the control group. The administration of taxol induced a significant reduction (P <0.01) of the sensory nerve conduction velocity compared to the control group; this reduction was dose-dependent: -17% with the dose of 16 mg / kg and -9% with the dose of 8 mg / kg. Treatment with acetyl-L-carnitine induced a statistically significant (p <0.01) increase in sensory nerve conduction velocity in both groups; 9% compared to the group of 16 mg / kg of taxol and 5% compared to the group of 8 mg / kg of taxol. Based on the results obtained, it will be observed that acetyl-L-carnitine is able to achieve a statistically significant protection against the neurotoxicity induced by taxol.

EXAMPLE 3 Protective effect of acetyl-L-carnitine on weight loss induced by taxol The animals used in the previous experimental model were weighed before starting the treatment (basal value) and at the end of the treatment. The data presented in Table 3 demonstrate the substantial and unexpected protective effect exerted by acetyl-L-carnitine on the loss of body weight caused by the treatment with taxol. TABLE 3 Body weight of animals treated with taxol alone or in combination with Acetyl L-carnitine.

The values are the mean ± the standard deviation. The number in parentheses is the number of animals used. Test t (independent data) • = p < 0.001 vs Pretended Test t (paired data) * p < 0.001; ** p < 0.01; *** p < 0.05 basal vs. EXAMPLE 4 Protective effect of acetyl-L-carnitine on taxol-induced neutropenia The inventors have stated that the neutropenic effect of taxol reaches a nadir after the third to fourth injection. To evaluate the action of ALC in combination with taxol, the degree of protection induced by ALC was evaluated in the treatment with taxol alone and in the animals inoculated with murine breast cancer cells (L-MM3), both in the amount of circulating neutrophils as in tumor growth, and tumor growth was evaluated in animals treated with ALC and taxol or with ALC alone. Treatment with taxol caused a significant reduction in polymorphonuclear cells. The oral administration of acetyl-L-carnitine combined with the taxol treatment proved to be able to significantly prevent the neutrophil granulocyte reduction induced by the anticancer agent. With respect to tumor growth, taxol, when injected in accordance with the same program used for the evaluation of neutrophil granulocytes, was found to significantly inhibit the growth of L-MM3, which was monitored until the tumor reached approximately 2 cm in size. The combined treatment with taxol and ALC for 14 days did not affect the action of taxol against cancer. In conclusion, in this tumor model, taxol caused a severe neutropenia and ALC, administered continuously in the period in which this type of toxicity to the bone marrow occurs, was able to prevent the taxol-induced reduction of polymorphonuclear cells. At the same time, the action of ALC had no effect on the activity of taxol against cancer. EXAMPLE 5 Effect of administration of acetyl-L-carnitine (ALC) in combination with taxol ip, on neutropenia in mice In a study conducted in accordance with Good Laboratory Practice (GLP), to evaluate the action of the acetyl-L-carnitine (ALC) in combination with taxol on the neutropenia induced by it, the animals were treated with ALC plus taxol and with taxol or ALC alone. In this model, the amount of circulating neutrophils was measured. It was found that taxol induces a significant reduction of neutrophil granulocytes in only 6 hours after the third injection and, in this way, a severe neutropenia occurs with a nadir after the third to fourth injection. An internal salt of acetyl-L-carnitine was used (sterile ampule), dissolved in water for injections. Each vial of ALC dissolved in 4 ml of injectable water (Solution O). Two ml of the solution (O) were taken to 25 ml with sterile PBS (Sigma), to obtain 10 mg / ml for subcutaneous administration (100 mg / kg / 10 ml); 0.8 ml of the solution (O) were taken to 50 ml with PBS in order to obtain 2 mg / ml for oral administration (100 mg / kg / 50 ml). Taxol (paclitaxel (INDENA)) was weighed, dissolved in the specific vehicle previously prepared ® (Cremophor EL (BASF), diluted 1: 1 with ethanol) and stored at + 4 ° C protected from light. At the time of use, the 12 mg / ml solution was diluted 1: 4 with saline in phosphate buffer solution (PBS) (SIGMA) and injected by i.p. (30 mg / kg / 10 ml).

The essential experimental indications are given below: Animals: female BALB / c mice of 18 to 20 g of body weight (Harian). Animal housing conditions: 4-5 mice per cage; temperature 22 ± 2 ° C; relative humidity 55 ± 15%; air changes 15-20 / h; light / dark cycle 12 h (light from 7:00 a.m. to 7:00 p.m.); Makrolon cages (26.7 x 20.7 x 14 cm) were used with stainless steel grid covers; without dust, sterile and with corn husk bed. Diet: food 4RF21 (company: Mucedola), food and water available "ad libitum". Randomization is casual in blocks of animals, i.e. the staff of the animal farm transfers the mice from the boxes to the cages, filling one cage at a time. In a second phase, the staff of the bioterium tentatively identifies all the mice, weighs them and, if the weights show significant differences between groups, moves the animals from one cage to another, keeping the number of animals per cage unaltered, to achieve weights well paired between the cages. Each cage was marked with a card that had the group number, the type of treatment (substance and / or injected substances, dosage, route of administration). Each animal was identified with a number from 1 to 5, written on the tail with indelible ink. Weight of the animals: the mice were weighed before starting the treatment and on day 5 or 7 and on day 11. The animals were treated from day 1 to day 10 with the molecules; the taxol or the vehicle were administered on alternate days, on days 5, 7, 9 and 11. The groups are: 1) white, 2) vehicle plus PBS; 3) taxol; 4) taxol + ALC; 5) ALC; 6) ALC + vehicle. The animals were sacrificed 6 hours after the last injection of taxol. Blood and bone marrow samples were taken 6 hours after the last treatment with taxol or vehicle. Mice were anesthetized with C02, blood was taken from the retroorbital plexus (0.5 ml of blood / mouse) and placed in Eppendorf test tubes containing 10 μl of Vister heparin (5000 U / ml). The animals were sacrificed by cervical dislocation. Subsequently samples were taken from the bone marrow. A blood sample and a bone marrow sample were taken per mouse at different times. Blood cell count Before starting the leukocyte count, the instrument was checked by measuring the parameters of an EMACHECK blood sample (human blood) provided by Delcon. The instrument was used in accordance with the instructions provided in the operation manual. The blood sample (25 μl) is taken from the dilutor and brought to a volume of 10 ml with isotonic solution (PLTA Saline, Delcon) in a beaker (dil. 1: 400) (Solution A). From solution A, the dilutor takes 100 μl and brings them to 10 ml (dil.1: 100) in another beaker (Solution B). Solution A is added with 3 drops of hemolytic agent (Emosol, Delcon), the solution is mixed by hand and allowed to act for approximately 2 minutes so that the erythrocytes break and the HGB (hemoglobin) is released. Solution A containing the hemolytic agent is used for the leukocyte count (WBC) and for the hemoglobin (HGB) readings. Solution B is used for the erythrocyte count (ERI) and platelet count (PLT). Duplicate readings were made in each sample and between one sample and the next the instrument was washed with isotonic solution. Superfrost plus slides were used (25 x 75 x 1 mm) (Mensel-Glaser) ready to use. The blood (8 μl) is deposited on the right side of the slide; another slide, placed at a 45 ° angle, to the left of the blood, is pulled back until it comes in contact with the drop, which disperses rapidly upon contact with the line between the two slides; The slide moves forward with a quick and smooth movement to obtain a thin film of blood. The film slide is allowed to air dry, stained with Diff-Quick (DADE) dye in accordance with the manufacturer's instructions and allowed to air dry again. The slides are immersed in Histolemon solution (Cario Erba) for 2 seconds; A drop of synthetic gum (Shandon) is placed in the center of the slide and a coverslip is placed on it to cover the whole blood smear, being careful not to bubble between the slide and the coverslip. The slides are allowed to dry and then the LEU count is made, up to 100, with an optical microscope, after having deposited a drop of cedar oil on the slide. The amount of LEU / ml, evaluated using a hemocytometer, is multiplied by the percentage value of the corresponding neutrophil granulocytes of the leukocyte formula. This parameter, divided by 100, expresses the neutrophil value / mm3 of blood. The following are considered as the values of normal parameters: pair LEU, counted in hemocytometer, values up to 18000 / mm3; for percentage of neutrophils, counted on slides, values of up to 18%; for absolute neutrophils calculated, values up to 1800. The data are expressed as the mean ± standard deviation. The comparison between the granulocyte neutrophil values obtained for the different groups was made using ANOVA. The abnormal values were subjected to the TDixon test. Treatment with taxol (30 mg / kg, ip every 2 days for a total of 4 times) caused significant neutropenia 6 hours after the last injection of the agent (-90% neutrophil granulocytes compared to the blank, p < 0.001). Oral or subcutaneous administration of acetyl-L-carnitine (100 mg / kg) was found to protect polymorphonuclear cells against damage induced by taxol by 8-43% s.c; -23% oral (Table 4). In another experiment, the combination of ALC + taxol caused a 73% reduction of neutrophils, against the 98% reduction obtained after the administration of taxol alone. The administration of ALC or vehicle + ALC did not cause alterations in the neutrophils compared to the vehicle alone or with the untreated animals (targets) (Table 4). The days after the administration of taxol, the neutrophil granulocytes began to recover (-64% vs vehicle), but the effect is still more marked after the combined treatment with ALC + taxol (-26% vs vehicle). In this case, the administration of ALC or the vehicle + ALC did not cause alterations in the neutrophils in comparison with the vehicle alone or with the untreated animals (targets (Table 5)) TABLE 4 Effect of ALC on the neutropenia induced by taxol in BALB / s mice The data is the mean ± standard deviation. **** P < 0.0001 vs vehicle; ooP < 0.05 vs taxol (ANOVA). TABLE 5 Effect of ALC on taxol-induced neutropenia in BALB / c mice The data is the mean ± standard deviation.

**** P < 0.0001 vs vehicle; ** P < 0.01 vs vehicle; P < 0.01 vs taxol (ANOVA). Taxol administered 4 times on alternate days induces severe neutropenia. The oral administration of ALC is able to achieve significant protection against the harmful effect of taxol. EXAMPLE 6 Effect of the administration of acetyl-L-carnitine (ALC) in combination with taxol iv, on neutropenia in mice Experiment 5 was repeated essentially, except for the route of administration of taxol, which in this case was intravenous that is, under the conditions of actual clinical application. The experimental calendars and the measurements were carried out in the same way as those described in the previous example. The results are presented in Tables 6 and 7. TABLE 6 Effect of ALC on taxol-induced neutropenia in BALB / c mice The data is the mean ± standard deviation. **** P < 0.0001 and P < 0.01 vs vehicle; ooooP < 0.0001 vs taxol (ANOVA).

TABLE 7 Effect of ALC on taxol-induced neutropenia in BALB / c mice The data is the mean ± standard deviation. **** P < 0.0001 and P < 0.01 vs vehicle; oooP < 0.0001 vs taxol (ANOVA). These results confirm the protective effect of ALC administered orally. EXAMPLE 7 Effect of administration of asetil-L-carnitine (ALC) in combination with taxol, on neutropenia in mice with breast L-MM * carcinoma and evaluation of the action against cancer In a study conducted in accordance with Good Laboratory Practices (GLP) to evaluate the action of acetyl-L-carnitine (CLA) in combination with taxol, on tumor growth in Balb / c mice, these mice were inoculated with murine mammary cancer cells (L-MM3 ) and the animals were treated with ALC plus taxol and with taxol or with ALC alone. In addition, in this tumor model, the amount of circulating neutrophils was measured. An internal salt of acetyl-L-carnitine (sterile ampule) dissolved in water for injections was used. Each vial of ALC was dissolved in 4 ml of injectable water (solution O). 0.8 ml of the solution (O) were taken to 50 ml with sterile PBS (SIGMA) in order to perform the oral administration (100 mg / kg / 50 ml). Taxol (paclitaxel (INDENA)) was weighed, dissolved ® in the previously prepared specific vehicle (Cremophor EL (BASF), diluted 1: 1 with ethanol) and stored at + 4 ° C protected from light. At the time of use, the 12 mg / ml solution was diluted 1: 4 with saline in phosphate buffer solution (PBS) (SIGMA) and injected by i.p. (30 mg / kg / 10 ml). The essential experimental indications are given below: Animals: 120 BALB / c female mice of 18 to 20 g of body weight (Harian).

Animal housing conditions: 5 mice per cage; temperature 22 ± 2 ° C; relative humidity 55 ± 15%; air changes 15-20 / h; light / dark cycle 12 h (light from 7:00 a.m. to 7:00 p.m.); Makrolon cages (26.7 x 20.7 x 14 cm) with stainless steel grid cover were used; without dust, sterile and with bed of corn husk. Diet: food 4RF21 (company: Mucedola), food and water available "ad libi tum". Randomization was casual in blocks of animals, i.e. the staff of the animal farm transfers the mice from the boxes to the cages, filling one cage at a time. In a second phase, the staff of the animal house provisionally identifies all the mice, weighs them and, if the weights show significant differences between the groups, moves the animals from one cage to another, keeping the number of animals per cage unaltered. Each cage was labeled with a card that had the group number, the type of treatment (substance and / or injected substances, dose, route of administration). Each animal was identified with a number from 1 to 5, written on the tail with indelible ink. Weight of the animals: the mice were weighed before starting the treatment and on the day of the last taxol injection.

Treatment program 1: transplantable murine cancer cells (LM 3) of Balb / c origin were grown at 37 ° C in plastic bottles with 5% C02 in a humidified incubator, in Dulbeco minimum essential medium (DMEM) containing 5% calf fetal calf serum (SFT) inactivated by heat, 2 mM L-glutamine and 80 μg / ml gentamicin. At the time of inoculation, the cells were detached from the bottle with trypsin-AEDT and resuspended in the same medium with PBS. Non-anesthetized female Balb / c mice received subcutaneous injections in the flank with 4 x 10 5 cells in 0.2 ml of DMEM. Four days after the inoculation of the tumor cells, the animals were treated with the molecules according to the following program, for the purposes of evaluating neutropenia: Day 1 Day 4 Day 8 Day 10 Day 12 Day 14 Inoculation Tax Tax Tax Tax of tumor cells ALC - > - »- > • - »- > ? - > - > - - - ^ - > - > • - Y. i Sacrifice after 6 h Then, ALC was administered for 10 more days and the animals were sacrificed after 6 hours.

The experimental groups, each consisting of 15 mice, were the following: Treatment program 2: the same experimental groups mentioned above, each consisting of 15 mice (with different numbers of cages) were treated in the following manner in order to evaluate the survival and size of the tumors. Day 1 Day 4 Day 8 Day 10 Day 12 Day 14 Day 17 ^ k < ^. ^ ^ L- ^ L ^ ^^ Tax Tax Tax inoculation of 'tumor cells' ALC - > - - - - - - > - > - »-» - »-» - > - > - »-» • LAC administration lasted 14 days (in groups 16, 17, 18) and tumors were measured until they reached a size of approximately 2 cm. The animals were left alive for 10 days. The experimental groups, each consisting of 15 mice, were the following: Cage Group No. Tumor + Vehicle 13, 14, 15 Tumor + Taxol + ALC 16, 17, 18 Tumor + Taxol 19, 20, 21 Tumor + Vehicle + ALC 22, 23, 24 Table of treatments and sacrifices Day Cage 1 Inoculation: 1, 4, 7, 10, 13, 16, 19, 22 Inoculation: 2, 5, 8, 11, 14, 17, 20, 23 Inoculation: 3, 6, 9, 12, 15, 18, 21, 24 4 ALC: 4, 16, 10, 22 5 ALC: 4, 5, 6, 16, 17, 10, 22, 11, 23 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23 , 12, 24 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23, 12, 24 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23 , 12, 24 Vehicle: 1, 13, 10, 22 Taxol: 4, 7, 16, 19 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23, 12, 24 Vehicle: 2 , 14, 11, 23 Taxol: 5, 8, 17, 20 10 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23, 12, 24 Vehicle: 1, 3, 13, 15 , 10, 22, 12, 24 Taxol: 4, 6, 7, 9, 16, 18, 19, 21 11 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23, 12, 24 Vehicle: 2, 14, 11, 23 Taxol: 5, 8, 17, 20 12 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23, 12, 24 Vehicle: 1, 3 , 13, 15, 10, 22, 12, 24 Taxol: 4, 6, 7, 9, 16, 18, 19, 21 13 ALC: 4, 5, 6, 16, 17, 18, 10, 22, 11, 23, 12, 24 Vehicle: 2, 14, 11, 23 Taxol: 5, 8, 17, 20 14 ALC: 5, 6, 17, 18, 11, 23, 12, 24, 16, 22 Vehicle: 1, 3, 13, 15, 10, 22, 12, 24 Taxol: 4, 6, 7, 9, 16, 18, 19, 21 Sacrifice 6 hours after the last administration of taxol in: 1, 4, 7, 10 + 3 animals white 15 LAC: 6, 18, 12, 24, 16, 22, 17, 23 Vehicle: 2, 14, 11, 23 Taxol: 5, 8, 17, 20 Sacrifice 6 h after the last injection of taxol in: 2, 5, 8, 11 + 3 animals white 16 ALC: 16, 22, 17, 23, 18, 24 Taxol: 6, 9, 18, 21 Vehicle: 3, 15, 12, 24 Sacrifice 6 h after the last injection of taxol in: 3, 6, 9, 12 + 4 animals white 17 ALC: 16, 22, 17, 23, 18, 24 18 ALC: 17, 23, 18, 24 19 ALC: 18, 24 The size of the tumors (length and width) was measured twice a week with a calibrator, from the moment the tumor was measurable. The size of the tumors was expressed in cm and was evaluated according to the following formula: (length x width). Tumor measurement program Day after inoculation Cage (comprising 5 mice) 22 13, 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 23 13, 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 28 13, 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 30 13, 16, 19, 22 14, 17, 20, 23 15, 18 , 21, 24 35 13, 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 36 13, 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 42 13 , 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 44 13, 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 49 13, 16, 19, 22 14, 17, 20, 23 15, 18, 21, 24 Blood and bone marrow samples were taken from the animals in the first treatment program. On the day they were sacrificed, the mice were anesthetized with C02, blood was taken from the retroorbital plexus (0.5 ml of blood / mouse) and placed in Eppendorf test tubes containing 10 μl of Vister heparin (5000 U / ml). The animals were sacrificed by cervical dislocation.

Subsequently, bone marrow samples were taken. A blood sample and a bone marrow sample were taken per mouse at various times. Hemic biometry Before starting the LEU account, the instrument was verified by measuring the parameters of an EMACHECK blood sample (human blood) provided by Delcon. The instrument was used in accordance with the instructions provided in the operation manual. The blood sample (25 μl) is taken from the dilutor and brought to a volume of 10 ml with isotonic solution (PLTA Saline, Delcon) in a beaker (dil. 1: 400) (Solution A). From solution A, the dilutor takes 100 μl and brings them to 10 ml (dil.1: 100) in another beaker (Solution B). Solution A is added with 3 drops of hemolytic agent (Emosol, Delcon), the solution is mixed by hand and allowed to act for approximately 2 minutes so that the erythrocytes are used and the HGB (hemoglobin) is released.

Solution A containing the hemolytic agent is used for the leukocyte count (WBC) and for the hemoglobin (HGB) readings. Solution B is used for the erythrocyte count (ERI) and platelet count (PLT). Duplicate readings were made in each sample and between one sample and the next the instrument was washed with isotonic solution.

Superfrost plus slides (25 x 75 x 1 mm) (Mensel-Glaser) ready for use were used. The blood (8 μl) is deposited on the right side of the slide; another slide, placed at a 45 ° angle, to the left of the blood, is pulled back until it comes in contact with the drop, which disperses rapidly upon contact with the line between the two slides; Then the slide moves forward with a fast and smooth movement to obtain a thin film of blood. The slide with the smear is allowed to air dry, stained with Diff-Quick (DADE) dye in accordance with the manufacturer's instructions and allowed to air dry again. The slides are immersed in Histolemon solution (Cario Erba) for 2 seconds; A drop of synthetic gum (Shandon) is placed in the center of the slide and a coverslip is placed on it to cover the whole blood smear, being careful not to bubble between the slide and the coverslip. The slides are allowed to dry and then the LEU count is made, up to 100, with an optical microscope, after having deposited a drop of cedar oil on the slide. The amount of LEU / ml, evaluated using a hemocytometer, is multiplied by the percentage value of the corresponding neutrophil granulocytes of the leukocyte formula. This parameter, divided by 100, expresses the neutrophil value / mm3 of blood. The comparison between the values of neutrophil granulocytes obtained from the different groups was performed using the ANOVA technique. Tumor sizes were compared using the nonparametric Mann Whitney test for unpaired data. Treatment with taxol (30 mg / kg, ip every 2 days for a total of 4 times) caused a significant reduction of polymorphonuclear (-93% vs vehicle, p <0.0001) in mice inoculated with murine mammary cancer cells 1 -MM3 The oral administration of acetyl-L-carnitine (100 mg / kg once a day for 10 days) combined with the treatment with taxol, showed the ability to significantly counteract the taxol-induced reduction of neutrophil granulocytes (335 / mm3 vs 65 / mm3, °° p < 0.01) (Table 8). Taxol, injected in accordance with the same program used for the evaluation of neutrophil granulocytes (30mg / kg, ip every two days for a total of 4 times), was found to significantly inhibit tumor growth L-MM3, the which was monitored until it reached a size of approximately 2 cm in the control group (0.5'6 cm vs 1.8 cm, p <0.0001). The combined treatment with the administration of CLA for 14 days (100 mg / kg once a day) plus taxol (30 mg / kg, ip every two days for a total of 4 times), did not affect the anti-cancer activity of taxol . In conclusion, in this tumor model, taxol also caused severe neutropenia and ALC, administered continuously in the period in which this type of toxicity occurs in the bone marrow, was able to prevent the reduction induced by taxol. polymorphonuclear At the same time, the action of the ALC did not affect the anti-cancer activity of taxol. TABLE 8 Effect of ALC on taxol-induced neutropenia in BALB / c mice inoculated with murine breast carcinoma (L- * ®43) The values are the mean ± standard deviation. **** p < 0.0001; *** P < 0.001 vs vehicle; °° P < 0.01; oooP < 0.001 vs taxol (ANOVA). Evaluation of the effect of acetyl-L-carnitine (ALC) on the action against cancer of taxol in murine lung cancer MI09 Taxol has proven to be effective in the treatment of ovarian, breast and lung cancer and in other types of cancer (Rowinsky , EK, and RC Doneho er, (1991); Pharmacol. Ther. 52:35). The action against cancer of this compound is mainly related to its ability to inhibit the depolymerization of microtubules in tubulin monomers (Schiff, P. B., J. Fant, and S.B. Horwitz, 1979, Nature); this effect blocks proliferating cells in the G2 / M phase of the cell cycle, i.e. between the last stage of the interface in which the synthesis of 7? DN is completed and the subsequent period of cell division or mitosis; and this leads, in the cell, to the beginning of a cascade of events typical of the apoptotic process. Taxol, similarly to other chemotherapeutic agents, is also associated with side effects such as neuropathies and myelosuppression. When comparing the statistical data obtained in the groups of animals treated with the vehicle alone and those treated with taxol in combination with the oral administration of acetyl-L-carnitine, a statistically significant reduction of the tumor mass was found at all time points. observed. In contrast, the comparison of the group treated with the vehicle alone and with the vehicle in combination with the administration of acetyl-L-carnitine, did not reveal statistically significant differences in the tumor mass at any of the time points observed. The analysis of the data referring to the comparison between the group treated with taxol and that treated with taxol in combination with acetyl-L-carnitine, did not show significant differences in the weight of the tumor. As regards the analysis of the number of metastases, the * data obtained show a statistically significant reduction of the number in the groups treated with taxol, with taxol in combination with acetyl-L-carnitine and with vehicle in combination with acetyl-L-carnitine, in comparison with the group treated with the vehicle alone. In particular, mice treated with taxol or with taxol in combination with acetyl-L-carnitine also showed a reduction in the diameter of the metastases compared to the groups treated with the vehicle alone or with the vehicle in combination with acetyl-L-carnitine . Based on the analysis of the following data, it can be established, therefore, that acetyl-L-carnitine does not interfere with the action against cancer of taxol in terms of inhibition of the tumor mass. In addition, acetyl-L-carnitine showed a significantly inhibitory effect on the formation of pulmonary metastases. The following example illustrates this additional aspect of the present invention. EXAMPLE 8 Evaluation of the effect of acetyl-L-carnitine (ALC) on the action against cancer of taxol in mice with lung cancer MI09 In a study conducted in accordance with Good Laboratory Practices (GLP) to evaluate the action of acetyl-L-carnitine (CLA) in combination with taxol on tumor growth, Balb / c mice were inoculated with murine lung cancer cells (M109) and animals they were treated with ALC plus taxol and with taxol or ALC alone. In addition, in this tumor model the amount of circulating neutrophils was measured. An internal salt of acetyl-L-carnitine (sterile ampule, 0.5 g) dissolved in water for injections was used. Each vial of ALC is dissolved in 4 ml of solvent (solution O). To be precise, 1.6 ml of solution 0 were taken to 40 ml with sterile buffer (PBS, Sigma P-4417) and then administered orally (100 mg / kg / 20 ml).

Taxol (paclitaxel (INDENA), key ® 3926570) was weighed, dissolved in the specific vehicle (Cremophor EL (BASF), diluted 1: 1 with ethanol) and stored at + 4 ° C, protected from light. At the time of use, the 12 mg / ml solution was diluted 1: 4 with phosphate buffer saline (PBS) (SIGMA) and injected i.p. (30 mg / kg / 10 ml). Animals: 60 female Ba, lb / c mice of 18 g of body weight (Harian). Animal housing conditions: 5 mice per cage; temperature 22 ± 2 ° C; relative humidity 55 ± 15%; air changes 15-20 / h; light / dark cycle of 12 h (light from 7:00 a.m. to 7:00 p.m.); Makrolon cages (26.7 x 20.7 x 14 cm) were used with stainless steel grid covers; no dust, sterile, with bed of corn husk. Diet: food 4RF21 (company: Muqedola), food and water available "ad libit? M". Randomization: causal in animal blocks. Weight of the animals: the mice were weighed before starting the treatment and then once a week until the end of the experiment. M109 tumor cells were isolated from a solid tumor.

The procedure described by Kedar E. B. Ikejiri, G.D. Bannard and R.B. Herberman (Eur. J. Cancer Clin. Oncol. 18; 991: 1982) with modifications. A Balb / c mouse (donor) was sacrificed by cervical dislocation and after washing its back with denatured alcohol, the dorsal skin was cut longitudinally into two flaps which were detached to remove the tumor mass. The latter was placed in a sterile gauze, where it was detached from the connective tissue and from necrotic and hemorrhagic parts. The study tissue was placed in a plate containing PBS with Ca ++ and Mg ++ (Gibco) at pH 7.2 and cold, cut into pieces of 2 to 3 mm and resuspended in a solution (15 ml of solution / g of tumor ) of PBS with Ca ++ and Mg ++, pH 7.2, containing 2 mg / ml of trypsin (type III, 10000 U / mg of protein, Sigma-Aldrich), 2 mg / ml of collagenase (type IS 180 U / mg of solids, Sigma), 0.2 mg / ml DNAse (type I 1548 U / mg protein, Sigma) and 25 μg / ml gentamicin (Sigma) and incubated at 37 ° C for 15 minutes under constant agitation. After, the cell suspension was homogenized with the aid of a mortar (B. Braun) for 2 minutes, incubated at 37 ° C for 10 minutes and gently aspirated a number of times with a syringe with sterile gauge needle no. 21. After the addition of 30 ml of RPMI-1640 (Eurobio) containing 10% fetal bovine serum (SFB) (Eurobio) maintained at 4 ° C, the cell suspension was filtered on a sterile gauze and then centrifuged at 700 g for 10 minutes. The cell pellet was gently resuspended with RPMI-1640 containing 10% FBS and 0.2 mg / ml DNAse (Sigma) and then centrifuged at 700 g for 10 minutes. The pellet was subjected consecutively to two washes with RPMI-1640; At the end of the last wash, the pellet was gently resuspended in RPMI-1640 to perform the count to establish the cell concentration. The cell count was performed under the microscope: it was carried out by means of a test for the exclusion of vital trypan blue staining; the tumor cells were adequately diluted with 0.4% trypan blue (Sigma), which is a vital stain that makes it possible to distinguish between viable cells and dead cells. The dilution containing the cells to be counted, was shaken gently, 10 μl was taken and used to prepare a Burker chamber. A square grid with three triple lines comprising 16 small squares (4 x 4) delimited one from the other by double lines was used. Both the viable cells (which had a translucent appearance) and the dead cells (which had a blue appearance because they had incorporated the staining) were counted inside the box formed by the median line and the triple lines, or on the line itself . This operation was repeated for three other frames, after which the sum of the cells in each frame was counted and the arithmetic mean was calculated for the readings taken in the four frames. The arithmetic mean of the viable cells was multiplied by the dilution factor used and by the specific power factor for the type of chamber used for the count (104), thus obtaining the number of viable cells contained per each milliliter. The ratio of the arithmetic mean of the viable cells to the arithmetic mean of the total cells, multiplied by one hundred, expresses the percentage of cell viability. Inoculation conditions: 60 non-anesthetized Balb / c mice of approximately 18 g body weight (Harian) received i.m. of 3 x 105 lung cancer cells M109 in 0.1 ml of RPMI-1640 (Sigma) in the right hind paw. Treatment program: for the purposes of evaluating the size of the tumors in the experimental groups, each consisting of 15 Balb / c mice, 3 x 10 ^ lung cancer cells M109 were inoculated and the molecules under study were administered in the times programmed. ALC was administered at a dose of 100 mg / kg (oral) from day 4 to day 17. The vehicle diluted 1: 4 with PBS of the stock solution was administered by i.p. on days 8, 10, 12 and 14. Taxol was administered at the dose of 30 mg / kg (ip) on days 8, 10, 12 and 14, as described in the following program: Day 1 Day 4 Day 8 Day 10 Day 12 Day 14 Day 17 inoculation with Tax Tax Tax Tax tumor cells ALC? - »- > ? - »-» - - »? - »-» - »-» The animals were kept under observation until day 22 after the inoculation of murine lung cancer cells MI09 and then they were sacrificed and their lungs were removed to determine the number of metastases. The experimental groups, each comprising 15 mice, were the following: Cage Group No. Tumor + Vehicle + ALC 1, 2, 3 Tumor + Taxol + ALC 4, 5, 6 Tumor + Taxol 7, 8, 9 Tumor + Vehicle 10 , 11, 12 Treatment table: DAY CAGE TREATMENT No. 1 Inoculation of 1,2,3,4,5,6,7,8 cells 2 ALC 1,2,3,4,5,6 3 ALC 1,2 , 3,4,5,6, 4 ALC 1,2,3,4,5,6 5 ALC 1,2,3,4,5,6 6 ALC 1,2,3,4, 5, 6 TAX 4 , 5,6,7,8,9 VEHIC 1,2,3,10,11,12 ALC 1,2,3,4,5,6 ALC 1,2,3,4,5,6 TAX 4,5 , 6,7,8,9 VEHIC 1,2,3,10,11,12 9 ALC 1,2,3,4,5,6 10 ALC 1,2, 3,4, 5, 6 TAX 4,5,6,7,8,9 VEHIC 1,2,3,10,11,12 11 ALC 1,2,3,4,5,6 12 ALC 1,2,3,4,5,6 TAX 4,5,6,7,8,9 VEHIC 1,2,3,10,11,12 13 ALC 1,2,3,4,5,6 14 ALC 1,2,3,4,5,6 15 ALC 1,2,3,4,5,6 Tumor measurement program: Day after inoculation Cage No. 4 1,2,3,4,5,6,7,8,9,10,11,12 8 1,2,3,4,5,6,7,8,9,10,11,12 11 1 2,3,4,5,6,7,8,9,10,11,12 13 1,2,3,4,5,6,7,8,9,10,11,12 15 1,2 , 3,4,5,6,7,8,9,10,11,12 18 1,2,3,4,5,6,7,8,9,10,11,12 20 1,2,3 4,5,6,7,8,9,10,11,12 Measurement of tumors: tumors were measured with a calibrator three times a week as soon as they were palpable. The tumor mass was calculated based on the measurements of the two dimensions (length and width), expressed in mm, according to the following formula: (length x width2) = volume of the tumor (mm3) 2 If we conventionally consider a tumor density equal to, the result is that the tumor volume expressed in mm3 is equal to the tumor weight expressed in mg. Determination of the number of lung metastases: on day 22 after the inoculation of murine lung cancer cells MI09, the animals under study were sacrificed by cervical dislocation. The lungs were excised and maintained for approximately 5 to 7 days in 5 ml of Bouin's solution with the following composition. 71% saturated picric acid solution (Merck) and 24% formaldehyde 10% (Fluka). When pulmonary metastases were evident, their number was counted. Statistical analysis of the data on tumor size and number of lung metastases was carried out using the nonparametric Mann-Whitney test for unpaired data. The analysis of the data obtained in the various groups of animals under study, showed the inhibition of the growth of the tumor mass in the group of mice treated with 30 mg / kg of taxol administered ip, in comparison with the mice of the treated group with the vehicle alone (Table 9). This phenomenon was already marked after only the first administration of the agent and the weight difference of the tumors between the group treated with taxol and that treated with the vehicle alone was statistically significant within a p < 0.01.

After the second administration, the reduction of the observed tumor mass was maintained, with a statistically significant difference (p <0.0001) in comparison with the group treated with the vehicle alone and this inhibition of the tumor mass was maintained after the following administrations- The group of animals treated with taxol administered ip at a dose of 30 mg / kg in combination with acetyl-L-carotin administered orally at a dose of 100 mg / kg, already showed a reduction in the growth of the tumor mass compared to the vehicle only after the first treatment, with a significance of p <; 0.05. This reduction also showed a tendency to maintain itself after the subsequent administrations. On all the days that the analysis was carried out, the group treated with the vehicle in combination with acetyl-L-carnitine did not show highly significant differences with respect to the growth of the tumor mass compared to the group treated with the vehicle alone. In addition, the comparison between the group treated with taxol alone and the one that received the combined treatment of taxol plus acetyl-L-carnitine, did not reveal statistically significant differences in the size of the tumor mass in any of the days analyzed. Based on the analysis of the following data, therefore, it can be established that acetyl-L-carnitine does not interfere with the action against cancer of taxol in terms of inhibition of the tumor mass. Regarding the analysis of the number of metastases at the end of the experiment, the data obtained show a statistically significant reduction in their number in the groups treated with taxol, treated with taxol combined with acetyl-L-carnitine and treated with vehicle combined with acetyl -L-carnitine, compared to the group treated with the vehicle alone. In particular, mice treated with taxol or with taxol combined with acetyl-L-carnitine, also showed a reduction in the diameter of the metastases compared to the groups treated with the vehicle alone or with vehicle plus acetyl-L-carnitine (see Table 10). Based on the analysis of the data obtained, it could be suggested that acetyl-L-carnitine has a moderate inhibitory effect on the formation of pulmonary metastases. TABLE 9 Effect of combined treatment of ALC + taxol on the growth of murine lung cancer MI09 in BALB / c mice Group Tumor size (mm3 ± SEM) Day 8 Day 11 Day 13 Day 15 Day 20 Vehicle 563 917 1137 1583 2305 ± 26 ± 59 ± 50 ± 62 ± 146 Vehicle 567 959 1289 1779 * 2251 + ALC ± 33 ± 50 ± 39 ± 57 ± 78 Taxol 539 662 ** 622 **** 357 **** 1085 **** ± 43 ± 50 ± 47 ± 70 ± 116 Taxol + 585 716 * 614 *** g ^ g **** 1202 **** ALC ± 25 ± 51 ± 61 ± 63 ± 72 Female BALB / c mice of approximately 20 g body weight received i.m. of murine lung cancer cells MI09 (3 x 10 5 cells / mouse). Tumors were measured in the days after the indicated inoculation. The animals were treated with ALC and taxol in accordance with the treatment program. The degree of significance was assessed by comparing the various treatment groups versus the group treated with the vehicle alone. * P < 0.05, ** P < 0.01; *** P < 0.001, **** P < 0.0001. The data were analyzed statistically using the Mann-Whitney test for paired data. TABLE 10 Determination of the number of lung metastases in the day 22 after inoculation of murine lung cancer cells M109, in BALB / c mice after combined treatment of taxol + ALC Group n animals (Average ± standard deviation size metastasis) Vehicle 6 109.3 ± 20.1 M, S 'Vehicle + 9 ** 77 ± 13.2 M, S ALC + Taxol 12 *** 9 ± 7.3 S + Taxol + ALC 13 *** 5 ± 2.4 S Female BALB / c mice of approximately 20 g body weight received i.m. of murine lung cancer cells M109 (3 x 10 5 cells / mouse). The animals were treated with ALC and taxol in accordance with the treatment program. On day 22 after the inoculation of the tumor cells, the animals were sacrificed, the lungs were removed and stored in Bouin's solution. The number of metastases was evaluated 10 days after the samples were taken. + The degree of significance was assessed by comparing the various treatment groups versus the vehicle-only group. * P < 0.05 vs. vehicle, ** P < 0.01; *** P < 0.001. The difference between taxol vs taxol + ALC was significant (P <0.05). The data were analyzed statistically using the Mann-Whitney test for paired data. M = medium (1-2 mm in diameter); S = small (<1 mm in diameter). ALC does not interfere with the therapeutic effect of taxol and this aspect was also evaluated in a human tumor model, as illustrated in the following example. EXAMPLE 9 Study of the influence of asetil-L-carnitine (ALC) on the anti-cancer activity of taxol in a human tumor model. Cell cultures of LOVO human colon cancer cells transplanted in bald mice were used. The tumor was inoculated into solid fragments on both flanks of the mice (day 0). The inoculated tumors were measured with a calibrator and when they reached a tumor weight of 100 mg (day 7), the animals were divided into four groups of 5 animals each, according to the following table: Group 1 Controls Group 2 taxol Group 3 ALC Group 4 taxol + ALC On the same day, the treatment with ALC began and continued for 18 consecutive days (qdxld) (groups 3 and 4). LAC was administered at a dose of 100 mg / kg with a volume of administration of 25 ml / kg. Taxol (54 mg / kg / 15 ml / kg) was administered i.v. in accordance with a program consisting of a total of 4 administrations at 4-day intervals (q4dx4; days 10, 14, 18, 22) (groups 2 and 4). Over the course of the treatment and in the following three weeks at four-night intervals, the tumors were measured and the tumor volume inhibition was calculated (% IVT, calculated as 100- (average weight of treated tumors / average tumor weight). control x 100)) as obtained with the various treatments. Treatment with taxol caused an inhibition of tumor growth (% IVT = 88%). Treatment with CLA had no effect on tumor growth, which was similar to that of tumors in the control group. The combination treatment of taxol plus ALC showed an efficacy against cancer (% IVT = 90%) almost identical to that achieved with taxol alone, which confirms that ALC does not interfere with the cytotoxic activity of taxol. EXAMPLE 10 Study of the influence of acetyl-L-carnitine (ALC) on pulmonary toxicity induced by bleomycin. Hamsters of 120 g of body weight were treated with bleomycin (1 unit) by the intrathecal (IT) administration route or with an equivalent volume of saline solution. In addition, the animals were previously treated with ALC (200 mg / kg) or with saline administered intraperitoneally just before the instillation of bleomycin, followed by daily injections for 1 week. The animals were allowed three weeks of recovery before taking the tissue samples. At the time the tissue samples were taken (day 22), one lung was prepared from each animal for histological investigation and the other lung was used for the quantitative determination of hydroxyproline. The experimental groups were organized as follows: 1. Previous treatment with saline / saline IT solution. 2. Previous treatment with saline / bleomycin IT. 3. Previous treatment with ALC / IT saline. 4. Previous treatment with ALC / bleomycin IT. Three experiments were carried out, in a total of 41 animals. The lungs were fixed by insufflation in 20 cm H0 ex vivo with 10% formaldehyde in PBS (pH 7), soaked with paraffin, cut and stained with hematoxylin / eosin. Sections with similar orientation of the portion of the upper, middle and lower lobes, respectively, were examined to verify the presence and degree of inflammatory infiltrate, interstitial and intraalveolar fibrosis and edema. The lungs that received saline solution or a previous treatment with ALC / saline IT, presented a normal alveolar morphology. The animals treated with bleomycin IT or with a previous treatment with saline alone, presented a dense fibrosis, alveolar atelectasis and edema. In animals previously treated with CLA, there were a number of fibrotic areas which, however, had a thinner appearance and less dense collapse areas. The content of hydroxyproline (one of the main constituents of collagen) was measured using the known Woessner method. Lung samples were homogenized, hydrolysed with NaOH and then allowed to oxidize before adding the Erlich aldehyde reagent. Aliquots were evaluated in duplicate of each sample by spectrophotometry and compared with a standard calibration curve obtained with purified hydroxyproline. The content of hydroxyproline (HYP) is expressed in mg / lung. The untreated hamsters or those treated with ALC alone showed levels of HYP compatible with the normal values accepted. The animals treated with bleomycin showed an increase in HYP consistent with the increase in collagen deposition during the fibrotic reaction. However, animals treated with CLA showed a reduction in HYP compared to those treated with bleomycin, which is consistent with an improvement in the fibrotic response.

HYP group Saline solution / saline 0.741 Saline solution / bleomycin 1831 ALC / saline 0.801 ALC / bleomycin 1.380 ALC causes a reduction in the fibrotic response in animals treated with bleomycin. EXAMPLE 11 Increase in anti-cancer activity of taxol in the presence of propionyl-L-carnitine (PLC) in vivo Cell cultures and tumor inoculation conditions. Cell cultures of murine mammary cancer cells L-MM3 cultured at 37 ° C in plastic bottles were used in a humid atmosphere with 5% C02. The cells were grown in DMEM supplemented with 10% SFT and in the presence of 2 mM L-glutamine and 80 μg / ml gentamicin. Cells in subconfluent layer were collected during the exponential growth phase using trypsin-AEDT and resuspended in DMEM. They were then injected subcutaneously in female Balb / c mice of 20 g of body weight, at a density of 4 x 10 A tumor measurement method.

The tumors were measured with a calibrator three times a week as soon as they were palpable. The tumor mass was calculated based on the measurements of the two dimensions (length and width), and expressed in mm, in accordance with the following formula: (length x width2) = tumor volume (mm3) 2 If we conventionally consider a density Tumor equal to, the result is that the tumor volume is equal to (mm3 = mg). Method of preparation of taxol. Agent used: taxol (paclitaxel INDENA). The agent was weighed, dissolved in the specific vehicle (12 mg / ml) and stored at + 4 ° C protected from light. At the time of use, it was diluted 1: 4 with saline solution in phosphate buffer (PBS, SIGMA) and injected.

Vehicle: Cremophor® EL (BASF). The cremophor was diluted 1: 1 with ethanol and stored protected from light. On the day of treatment, it was diluted 1: 4 with PBS. The animals were selected and treated in the manner described in the previous examples. Treatment conditions. Program A). The mice were treated i.p. with 30 mg / kg of taxol and 100 mg / kg PLC s.c., in accordance with the following program. A) Day Treatment 0 Inoculation of 400,000 cells / mouse 12 Administration of 100 mg / kg, s.c. of PLC 13 PLC 14 PLC 15 PLC + Taxol (30 mg / kg) 16 PLC 17 PLC + Taxol 18 PLC 19 PLC + Taxol 20 PLC 21 PLC + Taxol 22 PLC 23 PLC 24 PLC B) Day Treatment (0 Inoculation of 400,000 cells / mouse 4 Administration of 100 mg / kg, PLC sc PLC 6 PLC 7 PLC 9 PLC + Taxol 30 mg / kg i.p. 10 PLC + Taxol 11 PLC 12 PLC + Taxol 13 PLC 14 PLC + 15 PLC PLC 59 PLC In both treatment programs, the control and taxol and PLC groups were inoculated with the same number of cells. ,. In addition, the taxol treatment was administered in accordance with the same procedures and at the same times in both the group treated with taxol alone and in the group treated with taxol and PLC. Treatment with PLC, either alone or in combination with taxol, in treatment program A), started on day 12 after tumor inoculation and ended on day 24; in treatment program B), the treatment started on day 5 after the inoculation of the tumor cells and ended at the conclusion of the experiment, i.e. on day 59. RESULTS Experiment A) Animals with tumors / total number of animals Day Control Taxol Taxol + PLC PLC 19 8/13 6/13 4/12 4/12 22 10/13 6/13 6/12 6/12 25 11/13 7/13 6/12 9/12 28 12/13 9/13 6/12 11/12 36 13/13 11/13 7/12 12/12 46 13/13 11/13 8/12 12 / 12 Tumor size Day Control SE Taxol + PLC Taxol + PLC PLC 0 0 0 0 0 22 2.3010.23 0.810.4 0.410.3 0.6 + 0.3 25 3 ± 0.6 0.9610.4 0.5 + 0.32 1.2 + 0.38 28 3.9 + 0.6 1.410. 4 0.8 + 0.52 3 + 0.4 36 9.510.6 5.5 + 0.5 3.4 + 1.25 9.510.8 46 14.3 + 0.86 1111.5 7.6 + 2.15 15 + 1.1 When applying the nonparametric Mann-Whitney test for unpaired data, significant differences were found in all time points observed in the taxol + PLC group versus the control group, with a p < 0.003, and only at the last observed time point (day 46) did the level of significance decrease to p < 0.034 It should be noted that the values for the taxol group on day 46 were not significantly different from the values of the control group. Experiment B) Animals with tumors / total animals Tumor size Day Control Taxol Taxol + PLC PLC 0 0 0 0 26 0.4 + 0.2 0.110.6 000 0.410.3 31 0.6 + 0.3 0.2 + 0.2 000 0.5 + 0.3 37 1.9 + 0.8 0.45 + 0.2 0.050 + 0.050 1.3 + 0.6 41 3.1 + 1.3 1.750 + 1.1 0.110.060 2.2 + 1.0 45 3.59 + 1.3 2.250 + 1.1 0.4 ± 0.2 3.9 + 1.2 53 7.2 ± 2 5.000 ± 2.2 2 + 0.8 5.6 + 1.4 59 9.611.9 5.612.2 3.95011.5 8+ 2.2 The Wilcoxon statistical test was applied in this experiment, which revealed that only the control group had significant differences with respect to the taxol + PLC group with a p < 0.05. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (31)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. The use of a compound of the formula (I): wherein R is hydrogen or an alkyl group of 2 to 8 carbon atoms and X- represents the anion of a pharmaceutically acceptable salt, for the preparation of an edicament comprising an anticancer agent, characterized in that the compound produces a synergistic effect with the activity of the agent against cancer.
2. 2. The use according to claim 1, characterized in that R is a propionyl group.
3. 3. The use according to any one of claims 1 or 2, characterized in that the agent against cancer is taxol.
4. 4. The use according to any of claims 1 or 2, characterized in that the agent against cancer is bleomycin.
5. 5. The use of a compound of the formula (I): wherein R is hydrogen or an alkanoyl group of 2 to 8 carbon atoms and X- represents the anion of a pharmaceutically acceptable salt, for the preparation of an effective medicament in the reduction of metastasis.
6. 6. The use according to claim 5, wherein the treated tumor is a lung tumor.
7. 7. The use according to any of claims 5 or 6, characterized in that R is an acetyl group.
8. The use according to claim 1, and in particular the use of acetyl-L-carnitine or a pharmaceutically acceptable salt thereof, for the preparation of a medicament comprising an anti-cancer agent that is selected from the group consisting of of «taxol, carboplatin, bleomycin and vincristine, characterized in that the medicament is substantially devoid of the typical side effects of said agent against cancer.
9. 9. The use according to claim 8, characterized in that the agent against cancer is taxol.
10. 10. The use according to claim 8, characterized in that the agent against cancer is bleomycin.
11. 11. The use according to any of claims 8 and 9, characterized in that the side effect is neutropenia.
12. 12. The use according to any of claims 8 and 9, characterized in that the side effect is peripheral neuropathy.
13. 13. The use according to any of claims 8 and 10, characterized in that the side effect is lung damage.
14. 14. A combination, characterized in that it comprises taxol, acetyl-L-carnitine and propionyl-L-carnitine and, optionally, L-carnitine.
15. 15. The use of the combination according to claim 14 for the preparation of a medicament with anti-cancer activity, characterized in that the medicament exerts a synergistic action and is substantially devoid of side effects or only has limited side effects.
16. 16. A pharmaceutical composition characterized in that it comprises the combination according to claim 14 in a mixture with pharmaceutically acceptable carriers and / or excipients.
17. 17. A pharmaceutical composition according to claim 16, characterized in that it comprises a therapeutically effective amount of taxol together with a protective amount of acetyl-L-carnitine and a synergistic amount of propionyl-L-carnitine, and possibly L-carnitine, in a mixture with pharmaceutically acceptable vehicles and / or excipients.
18. 18. A combination characterized in that it comprises bleomycin and acetyl-L-carnitine and possibly L-carnitine.
19. 19. The use of the combination according to claim 18, for the preparation of a medicament with anti-cancer activity, characterized in that the medicament is substantially devoid of side effects, or only has limited side effects.
20. 20. A pharmaceutical composition comprising the combination according to claim 18, in a mixture with pharmaceutically acceptable carriers and / or excipients.
21. 21. A pharmaceutical composition according to claim 20, characterized in that it comprises a therapeutically effective amount of bleomycin together with a protective amount of acetyl-L-carnitine, in a mixture with pharmaceutically acceptable carriers and / or excipients.
22. 22. A package characterized in that it comprises a) a pharmaceutical composition comprising a therapeutically effective amount of an anticancer agent; b) a pharmaceutical composition comprising at least one compound according to claim 1 in an amount suitable to produce a synergistic effect with said agent against cancer; c) a pharmaceutical composition comprising at least one compound according to claim 1 in a suitable amount to produce a substantially protective action against the side effects of the anticancer agent.
23. 23. A package characterized in that it comprises a) a pharmaceutical composition comprising a therapeutically effective amount of an anticancer agent; b) a pharmaceutical composition comprising at least one compound according to claim 1 in an amount suitable to produce a synergistic effect with said agent against cancer.
24. 24. a package characterized in that it comprises a) a pharmaceutical composition comprising a therapeutically effective amount of an anti-cancer agent; b) a pharmaceutical composition comprising at least one compound according to claim 1 in an amount suitable to produce a substantially protective action against the side effects of said agent against cancer.
25. 25. A pharmaceutical composition characterized in that it comprises as active ingredients a therapeutically effective amount of an anti-cancer agent that is selected from the group consisting of taxol, carboplatin and vincristine, and a detoxifying amount of at least one compound of claim 1 or a of its pharmacologically acceptable salts.
26. 26. A composition according to claim 25, characterized in that the alkanoyl-L-carnitine is selected from the group consisting of acetyl-L-carnitine, propionyl-L-carnitine, butyryl-L-carnitine, valeryl-L-carnitine and isovaleryl-L-carnitine.
27. 27. A composition according to claim 25, characterized in that the pharmacologically acceptable salt of L-carnitine or alkanoyl-L-carnitine is selected from the group consisting of chloride, bromide, orotate, aspartate, acid, acid citrate, acid phosphate, fumarate and fumarate acid, maleate and acid maleate, acid oxalate, acid sulfate, glucose phosphate, tartrate and acid tartrate.
28. 28. The coordinated use of a therapeutically effective amount of an anti-cancer agent that is selected from the group consisting of taxol, bleomycin, carboplatin and vincristine, and a detoxifying amount of L-carnitine or an alkanoyl-L-carnitine in which the group alkanoyl is straight or branched chain and has from 2 to 8 carbon atoms, or one of its pharmacologically acceptable salts, to reduce the toxicity induced by the anticancer agent, while at the same time maintaining its effectiveness against cancer.
29. 29. The use according to claim 8, characterized in that the administration is sequential.
30. 30. The use according to claim 9, characterized in that the administration of the agent against cancer and L-carnitine or alkanoyl-L-carnitine is substantially simultaneous.
31. 31. A manufactured article characterized in that it comprises a pharmaceutical composition according to any of claims 16, 17, 20, 21, 22, 25, 26 or 27 accompanied by instructions for the simultaneous coordinated administration of the agents or for their administration in accordance with a predetermined dosing regime. PREPARATION OF MEDICINES WITH ACTIVITY AGAINST CANCER SUMMARY OF THE INVENTION The present invention relates to the use of an alkanoyl-L-carnitine of the formula (I) wherein R and X- are as defined in the description, in the preparation of medicaments useful for the treatment of tumors; in particular, the present invention relates to combinations of alkanoyl-L-carnitine and anti-cancer agents for the treatment of tumors, with an improvement in the therapeutic index and a reduction of the typical side effects of cancer chemotherapy.