WO2006043800A1 - Use of memantine for the prevention of neurotoxic reactions caused by antileukemic chemotherapy - Google Patents

Abstract

The invention relates to the use of memantine (chlorhydrate of 1-amino-3,5-dimethyl-adamantane) to prevent against adverse neurotoxic reactions caused by antileukemic chemotherapy, primarily in treatment schemes that include cytosine arabinoside (Ara-C or cytarabine), vincristine and/or L-asparaginase. The invention aims to satisfy the growing need for strategies that improve the effectiveness of anticancer treatments, by increasing the survival of patients affected and/or improving quality of life. Despite the fact that antileukemic treatment causes severe damage to the nervous system, there is currently no specific treatment intended to prevent said alterations which can sometimes be permanent or fatal.

Description

 USE OF MEMANTINE TO PREVENT NEUROTOXIC REACTIONS OF ANTILEUCÉWIICA CHEMOTHERAPY.

BACKGROUND OF THE INVENTION

The human central nervous system is the organ of consciousness, cognition, ethics and behavior, and as such, it is the most complex structure that exists, the synaptic neurotransmission being the predominant means by which neurons communicate with each other. This communication is mainly carried out by means of amino acids called neurotransmitters (acetylcholine, dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, glycine and glutamate). These are synthesized in the presynaptic region of nerve endings, where they are stored in vesicles and released into the space of synaptic connections by binding to specific receptors in postsynaptic cells [1,2].

The secreted neurotransmitters are eliminated by their recapture within the presynaptic neuron, by diffusion outside the intersynaptic space and / or by specific inactivation. When one or more of these neurotransmitter elimination mechanisms are altered or damaged, said amino acids accumulate in the intersynaptic space, becoming a toxic substance that can cause the death of neurons, this phenomenon is called excitotoxicity [ 3. 4].

Currently, attention has been focused on identifying the mechanisms of neurological damage of different origins and the relationship between them, including excitotoxicity, free radical formation, inflammation and programmed cell death (apoptosis), among others [5-8] .

Glutamate is the main excitatory neurotransmitter involved in rapid synaptic transmission, neuronal plasticity, development and survival, memory, learning and behavior [9-13]. Neurotransmitters modulate the function of postsynaptic cells by joining your specific receptors The most important glutamate receptors are the so-called N-methyl-D-aspartate (NMDA) receptors, since their binding with the neurotransmitter rapidly alters (in less than a millisecond), the electrical properties of postsynaptic cells, thereby producing the nerve impulse [14,15].

The N-methyl-D-aspartate receptors can be selectively activated by aspartate, homoquinolinate and quinolinate, in addition to glutamate and be non-competitively antagonized (that is, partially prevent this activation) by memantine [16]. This characteristic, of the memantine of being a non-competitive antagonist of the N-methyl-D-aspartate receptors, has allowed it to be a well tolerated drug, since it prevents the pathological activation of the N-methyl-D-aspartate receptors, but at the same time it retains its physiological functions, due to its moderate affinity with this receptor [17-19].

Memantine was first synthesized by researchers from the EI Lilly laboratories in order to prepare a derivative called N-arylsulfonyl-N'-3-5-dimethylated mantilurea, as an agent to lower blood sugar levels, but completely lacked such activity [16]. In 1972, the Merz company filed a German patent, demonstrating that this component (code D 145), has an activity in the central nervous system that confers a potential use for the treatment of Parkinson's disease, spasticity, coma and cerebrovascular disorders and geronto-psychiatric [20-24].

In 1975 and 1978, patents were granted in Germany and the United States, respectively. At that time, three of the best research groups were used for the biochemical, pharmacological and pharmacokinetic evaluation of D 145, which was given the generic name (INN) of memantine or memantine hydrochloride. In 1983, these groups published a review of memantine, in an attempt to summarize the experimental evidence to explain the clinical observations [25-27]. They postulated direct and indirect dopaminomimetic activity, as well as effects on serotonergic and noradrenergic systems. However, many of the data derived from experimental studies in cell cultures (//? Vitro) were obtained in concentrations 100 times higher than those used therapeutically, it should be mentioned that this fact was not recognized at that time [16] . Since then, extensive preclinical investigations of rnemantine have revealed that the most likely therapeutic mechanism of action is through antagonism of N-methyl-D-aspartate receptors (MMDA) [17, 28-31]. In 1989, Merz announced the application of memantine in the treatment of cerebral ischemia and Alzheimer's dementia. From this, clinical investigations have focused on the treatment of dementia [18, 32, 33].

One of the most complete recent reviews of mernantin was made by Parsons et al in 1999 [16]. This review of preclinical studies shows in detail the theoretical basis at a synaptic level of the therapeutic activity of rnemantine; both in vitro studies and in animal models. In addition to referring to the good clinical tolerance and tolerability in animal models of memantine, compared with other N-methyl-D-aspartate (NMDA) receptor antagonists, its therapeutic potential is mentioned in numerous disorders of the central nervous system , which varies from acute neurodegenerative processes (ischemia and trauma), chronic neurodegeneration (Parkinson's, Alzheimer's, Huntington's diseases, and amniotrophic lateral sclerosis) to symptomatic treatment (epilepsy, drug dependence, depression, anxiety and chronic pain). Similarly, new possible therapeutic applications of memantine are indicated, such as: acquired immunodeficiency syndrome (AIDS) [34, 35], glaucoma [36-38], hepatic encephalopathy [39], multiple sclerosis [40], tinnitus [ 41], tardive dyskinesia [42, 43] and spasticity [16, 44, 45].

However, in all the information that has been published to date, regarding the current or probable clinical applications of memantine, no its use is mentioned in the prevention of neurotoxic effects caused by

Ia antileukemic therapy.

Leukemia represents a serious public health problem worldwide, given its high mortality and its increasing incidence. It occupies the first place of infant mortality in our country and in many other countries, mainly in developing countries, adolescents and young adults constitute the second most affected population group with this disease [46-48].

In recent decades it has been possible to increase the survival of these patients with the combination of different chemotherapeutic drugs, the most important being vincristine, cytosine arabinoside (Ara-C or cytarabine) and L-asparaginase, among others. However, these medications are highly toxic, the nervous system being one of the most susceptible tissues to present serious and sometimes irreversible and / or fatal alterations [49-55].

Adverse reactions become more evident, when cerebral radiotherapy or drugs are applied together intrathecally (directly in the spine in order to reach high concentrations in the cerebrospinal fluid), with the purpose of avoiding the invasion of leukemic cells in the central nervous system [56-59]. }

There are several forms of chemotherapy: a) Induction, which is the initial intensive chemotherapy that is administered to eradicate the leukemic clone and induce complete remission (CR) [60], b) Post-induction (post-remission), is an additional chemotherapy that is administered after achieving CR in a major attempt to eradicate residual leukemic cells, although undetectable [61, 62]. This therapy includes the following stages: I) Consolidation II) Intensification and III) Maintenance [63]. There is currently no specific treatment aimed at protecting these patients from neurotoxic damage caused by antileukemic chemotherapeutic agents and / or radiotherapy. For this reason, the use of memantine is proposed in the prevention of neurotoxicity by antileukemic chemotherapy, an innovation that is intended to be protected by means of the present application, since the main use that memantine has had been for the treatment of neurodegenerative diseases such as Alzheimer's disease and other degenerative and vascular dementias.

DESCRIPTION OF THE INVENTION

As mentioned above, there is no specific treatment to date to prevent, reduce and / or reverse the neurotoxic reactions of antileukemic chemotherapy.

The specific characteristics and effectiveness of this novel treatment are clearly expressed in the following description and in the accompanying drawings, as well as a review of the figures shown.

Figure 1 shows the results of the spatial memory tests using the Morris water maze.

Figures 2, 3 and 4 show the results of the exploratory behavior tests by means of the hole platform or HoIe Board with different measurement parameters as explained in more detail later in this description, in the results section.

In order to prove that memantine is useful in the prevention of these neurotoxic damages, an experimental model with Swiss-Wistar rats was used. The main objective in this experimental design was, first of all, to cause neurological damage with the antileukemic chemotherapeutic agents that could be monitored and analyzed comparatively in different groups of animals in the various experimental conditions. Secondly, to demonstrate if there was a protective effect of memantine. In this way, it was thought to subject the groups of animals to cognitive tests, since in neurodegenerative diseases such as in Alzheimer's disease, the assessment of the efficacy of memantine is carried out through this type of studies.

Another advantage of using cognitive analysis is that the early manifestations of neurotoxicity are reflected precisely in a deterioration of these functions, which are regulated in a part of the brain called the hippocampus. This brain structure is more frequently related to the formation of short-term memory and learning.

To verify the hypothesis that memantine can prevent the neurotoxic damage of antileukemic chemotherapy, the following methodology was used: Animals. Swiss-Wistar rats, 8-week-old males weighing 120-140 g, were used, housed in polycarbonate cages with sawdust bed, light-dark cycles of 12:00 -12: 00 h, fed with balanced diet for rodents (Ralston-rations) and open water, under controlled conditions of temperature (22 ± 3 ^o C) and ambient humidity (70%). 4 groups of 10 rats were formed for each of the different experimental conditions.

Controls They did not receive pharmacological treatment, they were only injected with isotonic saline (0.9%) intraperitoneally, in the same volume as with the treatment and they were manipulated to introduce an esophageal cannula, following the same scheme of administration as for the other two groups, with the purpose of reproducing the influence of stress by injection and manipulation for oral administration, on the parameters analyzed in cognitive tests.

Treatments. Chemotherapeutic drugs from commercial laboratories, of most frequently used trademarks, were used, and the same treatments used regularly in practice were also implemented. clinic for leukemic patients. Subsequently, tests for cognitive assessment were carried out in order to establish the severity of neurological damage. During the entire treatment, a second group of 10 rats, in addition to the antileukemic treatment, received memantine in conventional therapeutic doses as described below, and with these animals the same tests were performed.

Cytosine Arabinoside The trademark CIT0SΛR-U ^{MR was used} . Experimental studies in rats have shown that the dose of 200 mg / kg produces survival and toxicity effects comparable to those resulting in 1 g / m ² in humans, this drug was used intraperitoneally [64,65].

Vincristine (Oncovin ^MR ). The dose was calculated at 500 μg / kg intraperitoneally, taking into account previous publications assessing the neurotoxic effects that resulted in rabbits with this same single dose intravenously, because rodents are more resistant to the neurotoxic effects of this drug than humans [66-68].

l-asparaαinase (Leunase ^MR ). 200 mg / kg were used intraperitoneally, previous studies have shown that this dose has caused brain effects in rats when administered every 8 hours for 2 days [69]; Its equivalence in humans is 500 IU / kg / day.

Memantine (Sigma Laboratories catalog number M9292). Doses of 10 mg / kg / d diluted in saline solution administered orally by means of an esophageal cannula, with a standard bolus of 0.5ml, were managed. Administration of this compound began 7 days before treatment with antileukemic drugs and continued during it [70, 71].

Treatment scheme:

A treatment scheme similar to that used in the induction chemotherapy of leukemia in humans was used. 10 rats were assigned for 4 study groups, with the doses described above:

1. Control group without treatment, receiving the same manipulation as the other experimental conditions. 2. Group with Memantine (days 1 to 14)

3. Group with chemotherapy. Cytosine arabinoside (days 8,11 and 14), Vincristine (day 9), L-asparaginase (days 12,13 and 14).

4. Group with memantine and chemotherapy.

Cognitive tests: These tests were performed with the purpose of evaluating spatial memory and exploratory behavior. These two functions are regulated by the brain structure called the hippocampus, which contains cells very sensitive to glutamate excess and therefore is very susceptible to alterations caused by the excitotoxicity phenomenon [72, 73]. For the study of memory and learning, the Morris water maze test was used, which is a technique that has gained wide popularity for its large number of publications where it has been used with various variables, including animal models of the disease of Alzheimer's [74-80]. Likewise, the hole field test (HoIe Board) was used, another technique widely used to assess the alterations of the exploratory behavior and locomotive activity caused mainly by drugs [81-87].

Field of holes (HoIe board). Once the treatment scheme was completed, the next day the hole field test (HoIe board) was performed. The test instrument consists of a hollow black acrylic cube of 60x60x60 cm and 5 cm above the floor of the box is a platform (table of holes) with 36 holes of 2.5 cm in diameter, distributed in a 6x6 cm matrix.

The hole table is divided by an imaginary line in a peripheral section (the line of holes in the perimeter of the table), and a central 4x4 holes. To initiate the test, the animal was placed in the center of the table of holes and for 15 min. its behavior was video-filmed and subsequently the following parameters were recorded:

—Percentage of time the animal spent in the central and peripheral areas of the table,

- total movement time and immobility,

- number of central, peripheral and total holes visited,

- frequency of visits (number of visits per minute of movement).

A hole is considered visited when the rat enters its head until the surface conceals the eyes. All the subjects under study performed the test the same day between 6:00 p.m. and 8:00 p.m.

Morris water maze (modified). This test was used to assess the spatial memory. It is a circular pool with 180 cm in diameter and walls 42 cm high painted black and divided into four imaginary quadrants, it is filled with water (20 ± 3 ⁰ C), up to a height of

23 cm, a black cylindrical exhaust platform with a diameter of 12.5 cm and 22 cm in height (invisible to the rat) is submerged inside, and it has a fixed location in one of the quadrants throughout the experiment.

The task is that the rat must swim in the labyrinth until the platform is located, -the first times by accident-, however; in subsequent sessions you must recognize your location site to be able to locate it, in this case; With the help of visual indicators of the context of the laboratory, as spatial keys, the brain functions involved to perform this task depend basically on the hippocampal activity.

For this study, the methodology described by de Queuerin, Roozendaal and McGaugh was followed with slight modifications [88]. The experiments were based on two types of trials; one of training and another of test, the training consisted of depositing the rat in the water from any starting site of the periphery and wait for a maximum of 60 s. to find the platform.

The time elapsed since the rat was deposited in the water until it located the platform was considered as an escape latency and its maximum duration was 60 s., If once this time was completed, the rat did not locate the hidden platform was guided until she and there remained for 20 s.

Subsequently, the rat was removed, dried and allowed to remain in the box with the other animals for 30 s., While the next trial began, and so on until completing 8 consecutive trials for each subject that same day, distributing in a balanced manner the starting sites of the first four trials between the four quadrants, so that each rat began its navigation from a different quadrant, but without following an orderly pattern, however; the random order of departure was the same for the second series of 4 trials, in this way, - each rat split twice from the same quadrant - Additionally; In the videotapes, the time that the rat sailed in the quadrant where the platform was located and in the opposite quadrant was recorded.

For the test trial (the next day; 24 h after the last training trial) the platform was removed, and each animal was introduced once in the pool from the same quadrant that was a lateral one, that is, neither the one of the platform, not the opposite. This starting point was the same for all animals. The rat was allowed to swim for 60 s. and withdrew from the maze. The time that the rat remained navigating in the quadrant where the platform was and in the opposite quadrant was recorded, as well as the times it crossed the site where the platform was. The test was carried out, between 7: 00-10: 00 am, was videofilmed and subsequently qualified by an observer who did not know the experimental conditions of the animals through a computer program specially designed for this purpose [89-92]. Results: The results of these experiments demonstrated on the one hand that chemotherapeutic agents mainly cause an alteration in spatial memory. The rats subjected to the combined treatment with cytosine arabinoside, vincristine and L-asparaginase, had difficulty remembering where the escape platform was on the first day of training. However, in the group in which the memantine was used preventively, this alteration was not observed and no differences were observed when compared with the control group without treatment or with the memantine group.

With reference to Figure 1, it is demonstrated that treatment with antileukemic agents causes an alteration in spatial memory and treatment with memantine prevents these alterations. The rats that only underwent treatment with antileukemic (T) chemotherapy had difficulty remembering where the escape platform was on the first day of training, once it was removed, there being a significant difference in relation to the other groups (* p <0.05). However, in the group with antileukemic chemotherapy and preventive treatment with memantine (MT), these alterations did not occur, and there were no significant differences in relation to the control group (C) and the group with memantine (M).

With respect to Figure 2, it corresponds to the results of the tests of the exploratory behavior by measuring the time in the central area by studying the Hole Platform or HoIe Board. The group of rats with antileukemic chemotherapy (T) remained less time in the central area of the hole platform (HoIe Board) compared to the other groups, being statistically significant (* p <0.05). This suggests that the group of rats undergoing chemotherapy presented high levels of anxiety, however, this effect did not occur in the group of rats with preventive treatment with memantine and chemotherapy (MT). In addition, this last group did not show significant differences with the control group (C) and with the group with memantine (M). Figure 3 corresponds to the results of the tests of the exploratory behavior, in this study the mobility time was measured by studying the Holes Platform or HoIe Board. In the group of rats with antileukemic treatment (T) a decrease in mobility was observed, which was statistically significant (* p <0.0001) compared to the other groups. This means that the excitability for the exploration was affected by the antileukemic treatment and again a protective effect was observed in the group under preventive treatment with memantine and chemotherapy.

(MT), there being no differences with the control group (C) and the group with memantine (M).

Figure 4. corresponds to the results of the tests of the exploratory behavior through the study of the Hole Platform or HoIe Board, here the total number of holes visited was taken into account. Memantine has been shown to protect cognitive disorders in conditions in which a deterioration in neuronal homeostasis is implicit. However, in the group of rats in which only memantine (M) was used, an increase in the total number of holes visited was observed, compared to the other groups (p <0.00O1), which means one that could influence some characteristics of exploratory behavior.

These experiments demonstrate that memantine prevents cognitive disorders related to the hippocampus, induced by chemotherapy with cytosine arabinoside, vincristine and L-asparaginase. In addition, it should be mentioned that these results strongly suggest that the neuronal damage induced by these treatments could be related to excitotoxicity events.

The experimental findings described above have important clinical implications for antileukemic chemotherapy and represent a therapeutic strategy that can be used in the short term. However, the current clinical experience that has been had with memantine is only in the treatment of Alzheimer's disease and other dementias, so its main application has been basically in the elderly. Likewise, these disorders are characterized by their chronic state and significant loss of nerve tissue due to cell death, mainly due to apoptosis. On the other hand, the treatment of this disease with memantine is carried out, at the moment in which there are signs and symptoms that make one suspect that the disease is present. By then, the neurological damage on the cerebral cytoarchitecture in most cases is very extensive, the reversibility of degenerative disorders being more difficult and slow. In the best case, it is only possible to stop neurodegenerative evolution preventing a greater deterioration of cognitive abilities in this type of patients.

In the early stages of Alzheimer's disease, the chances of reversibility of neuronal degenerative processes are much better. However, the perception of these demential disorders within the family nucleus and even for first-contact health professionals, becomes unnoticed in a large number of cases, delaying the timely treatment of this disease.

The proposal for the use of memantine, in the prevention of damage caused by antileukemic chemotherapy, is its use mainly in children, adolescents and young adults, because they are the population groups most affected by leukemia. Another important characteristic of this innovation is that memantine will be administered prior to the exposure of the causative agents of neurological alterations, during treatment with these neurotoxic drugs and in some cases, subsequent to it. This represents a very important advantage, in terms of the likelihood of therapeutic success, compared to the treatment of chronic neurodegenerative diseases, since the protective action of memantine will be carried out in intact neurobiological and neurochemical components or with Minimal alterations In this case, the neuroprotective capacity of memantine on the elements responsible for maintaining neuronal integrity will be much more effective.

The neurological damage mechanisms generated by the most commonly used antileukemic therapeutic schemes have not been satisfactorily studied, so there is no specific treatment for the prevention of said neurotoxicity. Epidemiological studies in the control of these diseases are based on cataloging as "complete success" an increase in survival and the absence of leukemic cells in cytological studies. However, the neurological sequelae caused by chemotherapy are not carefully evaluated. In this way, the neurological damage can last despite the fact that the oncological disease reaches a complete remission.

When a very important neurotoxic adverse reaction is detected with the antileukemic drugs, which endangers the patient's life, the doses of these drugs have to be reduced or said treatment discontinued and institute another alternative rescue treatment. However, when this happens, the prognosis for these patients is less favorable, since the treatment schemes used in induction therapy (that is, those that are initially used for the purpose of causing a complete remission eliminating the leukemic clone) They are the ones that have proven to be most effective.

Toxicological studies carried out to date with antileukemic drugs are experimentally performed in laboratory animals to measure the capacity of damage caused by each individual agent, however, in clinical practice they are never used separately to avoid the resistance of cancer cells to chemotherapy. This is one of the reasons, for which little is known about the mechanisms of neurological damage involved in the current combined antileukemic chemotherapeutic schemes. Therefore, with the introduction of the prophylactic application of memantine to the schemes of antileukemic treatments, the incidence of neurotoxic effects in patients under this type of chemotherapy will be significantly avoided or reduced. These patients, for some circumstantial reason inherent to their biological characteristics (for example, with a history of neurological or psychiatric disorders), are predisposed to present these collateral effects early thus reducing their chances of survival and / or presenting a significant deterioration in Your quality of life.

Another innovative advantage of the use of memantine as a protector of neurotoxicity caused by antileukemic drugs, is that the doses of these medications may be increased during the induction stage, which is the initial intensive chemotherapy and where neurotoxic effects occur more frequently. more serious In this way, on the one hand the chances of early undesirable effects are reduced, creating a greater tolerance in the cells of the nervous system and at the same time the anticancer effects of the chemotherapy in question are increased, reducing the risks of antileukemic cell resistance to said drugs

On the other hand, the cycles of antileukemic treatment must be carried out in a hospital and on many occasions the time spent in said medical care centers depends on the severity of the side effects that occur after induction chemotherapy. The vast majority of these undesirable effects are related to alterations in the nervous system.

The hospital stay represents a considerable economic waste affecting the family and state economy and at the same time, in leukemic patients the incorporation to daily and work activities is delayed, when it is young adults of economically productive age. In this regard, prophylactic treatment with memantine in patients undergoing antileukemic therapy can reduce hospitalization costs by shortening the length of hospital stay due to neurotoxial adverse reactions derived from said chemotherapy.

Memantine is a drug that has been marketed in our continent a short time ago, although it has been used in European countries for approximately 30 years. Its main indication, as mentioned above is in the degenerative dementia type Alzheimer and other mixed forms of degenerative and vascular dementia. Although the possible clinical applications of memantine have been disseminated by different means, based on experimental studies in animals and cell cultures, the use of this drug as a preventive drug for neurotoxicity caused by antileukemic chemotherapy has not been published previously.

The application of this therapeutic innovation in the pharmaceutical industry opens up new commercial possibilities for a drug that has already been approved for use in humans. Although its use as an antileukemic adjuvant, is a new therapeutic indication, the safety and tolerance that memantine has shown in all the years that it has remained in the market, it places it in an advantageous position when compared to some other molecule new or similar that was being studied for this same purpose.

In addition, it is important to mention that patients affected by leukemia constitute a much larger population than individuals affected with Alzheimer's disease, therefore the possibilities of commercialization are on a much larger scale than with the therapeutic indications originally used. Likewise, an individual with acute untreated leukemia may die within a few months (usually 2 months), while degenerative demential diseases tend to be chronic and the mortality of these patients is due to the majority of Sometimes to pathological conditions other than chronic neurodegenerative disease.

As described above, the scientific, economic, social and commercial perspectives of memantine can be estimated using it in the prevention of neurotoxic effects caused by antileukemic therapy, the characteristics of which tend to satisfy a priority health need worldwide.

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Claims

REINVINDICATIONS Having sufficiently described my invention, I consider it as a novelty and therefore as much as my exclusive property, the content of the following clauses: 1. The use of memantine (1-amino-3,5-dimethyl-adamantane hydrochloride), for the preparation, preparation or manufacture of a medication that helps prevent, reduce and / or reverse the neurotoxic effects caused by the treatment with the antileukemic chemotherapy, mainly in the treatment schemes in which drugs are included in which its neurotoxic effect has been proven, such as, for example, cytosine arabinoside (Ara-c or cytarabine), vincristine and L-asparaginase, among others. 2. A solid medicine to prevent, reduce and / or reverse the neurotoxic effects caused by treatment with antileukemic chemotherapy, characterized by being memantine of 5 to 10 mg and excipient of 90 to 500 mg. 3. A solid medicine to prevent, reduce and / or reverse the neurotoxic effects caused by treatment with antileukemic chemotherapy according to clause 2, characterized by being a 5 mg memantine and a 95 mg excipient. 4. A solid medicine to prevent, reduce and / or reverse the neurotoxic effects caused by the treatment with antileukemic chemotherapy according to clause 2, characterized by being 10 mg memantine and 90 mg excipient. 5. A liquid medicine to prevent, reduce and / or reverse the neurotoxic effects caused by treatment with antileukemic chemotherapy according to clause 2, characterized by being 50 to 100mg memantine and an excipient of 1 to 1 OOml. 6. A liquid medicine to prevent, reduce and / or reverse the neurotoxic effects caused by chemotherapy treatment antileukemic according to clause 5, characterized by being 100mg memantine and 10OmI excipient. 7. A liquid medicine to prevent, reduce and / or reverse the neurotoxic effects caused by treatment with antileukemic chemotherapy according to clause 5, characterized by being 100mg memantine and 5ml excipient. 8. A liquid medicine to prevent, reduce and / or reverse the neurotoxic effects caused by the treatment with antileukemic chemotherapy according to clause 5, characterized by being 50mg memantine and 1ml excipient. 9. A method to prevent the neurotoxic effects caused by the treatment with antileukemic chemotherapy, characterized by the following stages. a) Calculation of the dose. The administration of memantine orally or subcutaneously, will be done in doses that can range from 0.5 mg / Kg / d to 30 mg / Kg / d according to the scheme of chemotherapeutic antileukemic treatment in question (For example, in combinations of the antileucérnicos agents in which two or more drugs with recognized neurotoxic effect are included, higher doses of memantine will be used.In the same way, the doses will be increased, in the cases of patients with concomitant neurological disorders that by their characteristics, it is expected an potentiation of the neurotoxicity of the antileukemic chemotherapy). b) Impregnation stage. It refers to the administration of memantine prophylactically 7 days before starting treatment with antileukemic chemotherapy. This stage will be considered as the "habituation" or "impregnation" stage and half of the dose of memantine will be used, which is calculated as the ideal dose for each particular case. The purpose of using this method with a lower dose, is to induce a certain degree of tolerance on the part of the patient to memantine and in this way can identify and / or reduce adverse reactions by this drug. At the same time, at this stage it can be manifested, discovered and sometimes the sensitivity of each patient to memantine can be predicted, and adjustments of the dose can be made if necessary. c) Protection stage. It refers to administration of memantine during the application of induction antileukemic chemotherapy. In this stage, which will be considered as a "protection stage", the total dose of memantine calculated in each particular case will be used, which is equivalent to twice the dose of the previous stage. In this phase, the maximum neuroprotective effect is needed, since, as mentioned above, induction chemotherapy is the initial chemotherapy that is used to eradicate the leukemic clone and where the higher doses of chemotherapeutic agents are managed. In addition, this period is where neurotoxic reactions occur most frequently. This stage can last approximately 2 to 4 weeks, depending on the scheme of antileukemic treatment, and as in the previous stage, the dose of memantine can be adjusted in the cases that are required. The dose adjustments of the memantine will be carried out at any time of the impregnation stage or the protection stage, either to decrease the dose of the memantine in the cases in which adverse reactions attributable to the administration of said drug, mainly in the impregnation stage. Or, to increase the dose of memantine, in cases where neurotoxic adverse reactions attributable to antileukemic chemotherapeutic agents are observed, mainly in the protection stage. d) Support stage. It refers to the administration of memantine during the application of post-induction antileukemic chemotherapy (consolidation, intensification and maintenance). This stage will be considered as a "support stage" and includes the application of the memantine during the period after the Induction chemotherapy in which generally the doses of chemotherapy are decreased or the scheme of antileukemic treatment is changed. The duration of treatment with memantine and the doses used during this stage, will depend largely on the antileukemic drugs that are continued during this phase, on the therapeutic response of the patient affected by leukemia and on the neurological manifestations experienced during this period.