MXPA98009259A - Aspenate of adenosine, its method of preparation from adenosine, and its use for the preparation of medicines for the treatment of fibrosive hepatic diseases and pharmaceut composition - Google Patents

Abstract

The present invention relates to: A method for the preparation of adenosine aspartate from adenosine, pharmaceutical composition containing them and uses thereof for the treatment of patients with fibrosing liver diseases, such as cirrhosis and chronic hepatitis, of any type etiology and that are frequently accompanied by hepatic dysfunction, hemodynamic and hematological alterations, as well as signs of progressive encephalopathy. This use involves the administration of adenosine or a more soluble derivative, in the form of the salt of enteral adenosine aspartate, in sufficient quantities and times to reduce cell necrosis, stop fibrogenesis, increase the removal of scar tissue, normalize the Hepatic cellular deoxidizing-reducing state, and thus stimulating the regenerative capacity of the diseased tissue, which is heavily damaged in the fibrotic liver. This invention includes the treatment with adenosine or adenosine aspartate in early stages of hepatopathy that involve evident hepatocellular necrosis and / or alterations of the hemodynamic type, such as portal hypertension. The proposed treatment can be given simultaneously, or alternately, with anti-viral treatments, or with molecules considered hepatoprotective as zinc, selenium or poly-unsaturated lecithins. This method is proposed as a possible alternative to liver transplantation

Description

METHOD FOR PREPARING ADENOSINE ASPARTATE FROM ADENOSINE, PHARMACEUTICAL COMPOSITION CONTAINING THEM AND USES OF THEM IN THE TREATMENT OF FIBROSIVE HEPATIC DISEASES TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel use of adenosine and its derivative adenosine aspartate as hepatotrophic agents for the preparation of medicaments in the treatment of fibrosing liver diseases that can cause liver dysfunction and chronic encephalopathy. Also, the invention provides an alternative route for the treatment of liver cirrhosis by obtaining the active compound and preparing a pharmaceutical composition containing it, which has an important commercial value in the pharmaceutical industry and therapeutic application in the field of medicine. .

INTRODUCTION Hepatic fibrotic diseases that degenerate in cirrhosis are characterized by cellular damage, diffuse fibrosis and regeneration nodules with loss of the lobar and vascular architecture of the hepatic parenchyma. The most common causes of hepatic fibrotic disease are chronic alcohol consumption, viral infections of the hepatitis type (HVB, HVC) and as a consequence of chronic cholestasis or biliary tract disease. Less frequently, these pathologies are due to autoimmune diseases, venous congestive heart disease or to metabolic (genetic) disorders, such as Wilson's disease, glycogenosis, porphyria, galactosemia, etc. Alcohol is the most frequent cause of cirrhosis in the western world, since it accounts for 60% of cases and affects mainly male subjects between 40 and 60 years of age. The second cause of this disease is chronic viral hepatitis, especially the HVC type, which is responsible for more than 90% of cases of post-blood transfusion hepatitis, which evolves in almost 40% to cirrhosis. In Mexico, cirrhosis occupies the second cause of death in the population of productive age (45 to 65 years) and deaths from liver disease of any etiology represent 6% of the national total. Despite the advance in the knowledge of hepatic fibrotic diseases, there is no curative treatment of pharmacological type.

BACKGROUND OF THE INVENTION The present invention refers to the use of the enteral administration of adenosine aspartate, prepared from adenosine to restore the proliferative capacity of the liver tissue, thus stopping the fibrogenesis that occurs in liver disorders that end in cirrhotic symptoms, without import the etiological agent. The cirrhotic liver results from the imbalance of both the existing collagen, as well as that which is synthesized de novo and its degradation. This picture is accompanied by the presence of nodules that sequester liver cells in regeneration, isolating them in extensive areas of fibrosis. These findings indicate that the liver regenerative process is severely altered in an adverse way (Stocker and ullstein. "Capacity of liver regeneration after partial hepatectomy in cirrhotic ..." Liver Regeneration After Experimental Injury. New York Stratton, 66-74. 1973). Therefore, it is expected that the regenerative response would be deficient when the fibrosis begins to settle in the liver tissue. When multilobar necrosis occurs, the hepatic regenerative response is triggered by the proliferation of a group of cells that have characteristics similar to biliary cells, which could be dedifferentiated cells (hepatocytes), or may be due to the presence of pluripotent cells, which They are not normally found in the proliferative response that follows the surgical loss of healthy liver tissue (Callea et al., "Cirrhosis of the liver." A regenerative process. -Dig. Dis. Sci., vol 36, 1287-1293. The latter is confirmed by the discovery that liver regeneration is delayed when there is epithelial damage, such as occurs in the cirrhotic liver.; in such a way, there is an inverse correlation between the index of fibrosis in the liver and its regenerative capacity (Macintosh et al., "Hepatic fibrosis as a predictor of hepatic regenerative ..." Hepatology, vol.17, 307-309, 1992) . The physio-pathological mechanism involved in the generation of hepatic fibrotic symptoms is still unknown in its entirety. However, it is known that hepatocellular necrosis plays an important initial role in fibrogenesis, and is demonstrated by the significant increase in the liver "escape enzymes" that occur in cirrhotic patients. This event is gradually accompanied by a deficient hepatic function, which highlights the decrease in the serum availability of albumin (which produces generalized edema), and alterations in coagulation (due to the lack of hepatic synthesis of the coagulation factors) (Van Eyken et al. "A cytokeratin-immunohistochemical study of nodular focal ..." Liver, vol.9, 372-377, 1989). This deficient function of the liver favors the increase in the free pool of the precursor in the synthesis of collagen (proline), increasing the synthesis of this protein as the main element of the extracellular matrix. In fact, the synthesis of de novo collagen is greatly increased in experimental animals that are induced by cirrhosis and this effect is accompanied by a poor removal of collagen tissue already deposited. The latter is due to a decrease in the amount or activity of enzymes responsible for the degradation of collagen (collagenases), and / or changes in the structure of the collagen (amount of aldehydes and glycosaminoglycans), which promotes that said collagen was less susceptible to its enzymatic degradation (Pérez-Tamayo. "Is cirrhosis of the liver experi entally produced ..." Hepatology, vol 3, 112-120, 1983). The latter would explain why cirrhosis is practically irreversible, despite the removal of the harmful agent that promotes cell necrosis. The role of energy metabolism and intracellular oxide-reduction (redox) reactions in the hepatocyte, as a target of fibrogenic agents, has not been elucidated either. However, it has been suggested that a decrease in the hepatic energy burden in the cirrhotic liver may lead to a lower synthesis of hepatic albumin; however, there is also evidence that the production of albumin by the cirrhotic liver is not altered (Jikko et al., "Adenylate energy charge and cytochrome a in the cirrhotic ..." J. Surg. Res., vol.37, 361-368. 1984). On the other hand, in experimental cirrhosis it has been demonstrated that there are alterations in the redox state, both cytoplasmic and mitochondrial of the hepatocytes. These changes in the redox state promote a metabolic acidosis that leads to the synthesis of the collagen precursor (proline) and the subsequent hydroxylation of said proline in the synthesis of collagen, in such a way promoting its deposition in a liver tissue with a damaged regenerative capacity (Hernández-Muñoz et al. "Possible role of cell redox state on collagen metabolism ..." Biochim, Biophys, Acta, vol.1002, 93-99, 1994). The effects described above are the result of a progressive mitochondrial dysfunction that accompanies the fibrogenic process. In this context we have found that during the induction of experimental cirrhosis, mitochondria isolated from these livers show a decrease in oxygen consumption, a decrease in respiratory control and a poor use of ADP, the latter being what would promote a poor synthesis of ATP, by the mitochondria of cirrhotic livers (Hernández-Muñoz et al. "Effects of adenosine administration on the function ..." Arch. Biochem. Biophys., vol, 294, 160-167, 1992). In sum, accelerated hepatocellular necrosis, not accompanied by efficient restorative cell proliferation, promotes mitochondrial dysfunction. The changes of the redox state, together with the low mitochondrial synthesis of ATP, promote the availability of substrates for extracellular matrix synthesis. The fact that this accelerated synthesis of collagen is not followed by a remodeling of the hepatic stroma (due to deficient collagenolytic activity), propitiates the healing of large areas of the liver parenchyma, leading to hepatic fibrosis and, even, cirrhosis. experimental, and those found in patients with various liver diseases. Although several therapeutic approaches have been used to try to stop and reverse the fibrotic process, cirrhosis continues to be considered as an irreversible type of picture that gradually progresses to the death of the patient. These therapeutic measures have included diets with low fat content and vitamin supplements; antifibrotic-type medications that have side effects such as diarrhea and gastritis. Anti-inflammatories such as steroids, in order to inhibit the synthesis of collagen, but which produce adverse effects such as hyperglycemia, glaucoma and arterial hypertension. More recently, S-adenosylmethionine has been used as a hepatoprotector, promoting an improvement in the hepatic steatosis (fatty liver). The only method currently chosen for the treatment of cirrhosis is orthotopic liver transplantation, which has shown a survival of 70% a year after surgery. Its obvious disadvantages are the lack of donors and the cost of the procedure. In the model of experimental cirrhosis induced by the chronic administration of carbon tetrachloride to the rat, the administration of adenosine has given beneficial results in the control of this pathology. The administration of adenosine (200 mg / kg of weight) during the induction of experimental cirrhosis, reduces collagen accumulation, notably improving the histological picture of the cirrogenic process. This effect is accompanied by a marked improvement in liver function tests and energy parameters of the liver. The remodeling of the extracellular matrix seems to be due to an increased activity of collagenase. The increase in the availability of cellular energy and the collagenolytic activity of the fibrotic liver, induced by the administration of adenosine, is related to a normalization of the intracellular redox state, due to a protection of mitochondrial function (Hernández-Muñoz et al. " Adenosine partially prevents cirrhosis induced ... "Hepatology, vol 12, 242-248, 1990) and (Hernández-Muñoz et al." Balance between oxidative damage and proliferative potential ... "Hepatology, vol 26, 1100-1110,1997 ). All these changes promote an accelerated hepatic proliferative response, which is strongly depressed in the cirrhotic liver. The results already mentioned have led us to test adenosine and its more soluble derivative, which is adenosine aspartate (50 mg / kg of weight) as a possible reversal of a previously induced cirrhosis in the rat. The results obtained are that the cirrhosis is reversible up to 70% with 20 doses of the proposed compound, accompanying this effect of a complete normalization of the global hepatic function, the mitochondrial function and the stimulation of a regenerative process completely abolished in the liver cirrhotic These latter data give the advantage of considering that the cirrhotic process is potentially reversible, probably also in patients. Aspartate adenosine has a greater bioavailability for the treatment of liver diseases, since it is rapidly metabolizable without compromising liver function, this fact constitutes the main contribution of the present invention, given that current pharmacological treatments have not been reported as potential inducers of the hepatic proliferative process OBJECTIVES OF THE INVENTION One objective of the present invention relates to the treatment of fibrosing liver diseases, by the use of adenosine and / or adenosine aspartate. Another object of the invention is to provide a method for the preparation of the adenosine aspartate salt by the reaction of adenosine and aspartic acid. A further advantage of the invention is to provide a pharmacological compound such as adenosine aspartate, which is rapidly metabolizable, so that this leads to a better and faster assimilation of said compound for the treatment of fibrosing liver diseases. Also provided in the present invention are pharmaceutical compositions containing adenosine and / or adenosine aspartate in therapeutically effective amounts for the treatment of fibrosing liver diseases. Also, as its therapeutic uses that allow the reduction of hepatocellular necrosis, the arrest of fibrogenesis, the increase of the scar tissue removal, the normalization of the hepatic cellular redox state and the stimulation of the regeneration of a fibrotic liver with deep impaired liver function. It is also proposed that the nucleosides of the present invention can be used as an alternative to liver transplantation or as a preparation for a successful achievement of said surgical procedure. Thus, in the present invention is disclosed the process of preparation of adenosine aspartate from adenosine, pharmaceutical composition containing them and uses thereof in the treatment of fibrosing liver diseases.

BRIEF DESCRIPTION OF THE FIGURES Other objects, features and advantages of the invention will be apparent from the following detailed description, from the preferred embodiments, from the appended claims and from the accompanying figures, wherein: Figure 1, represents the liver incorporation of [1C] adenosine or [14C] adenosine aspartate, after oral administration at the same concentration (50 mg / kg body weight) in normal animals; Figure 2 shows the percentage of survival in animals subjected to toxic fulminant hepatitis, by the administration of carbon tetrachloride (2.5 ml / kg of weight); Figure 3, indicates in cirrhotic animals (30 doses of 0.15 ml / kg of carbon tetrachloride), the increase in the amount of collagen (more than 5 times over the control) and the reversal effect of both adenosine and aspartate of adenosine (4 and 8 weeks); Figure 4 shows the liver function, measured as the serum activity of escape enzymes and the amount of albumin and bilirubin in cirrhotic animals, and the effect of adenosine aspartate; and Figure 5 shows the activity of thymidine kinase in liver samples, as a marker of cell proliferation, in cirrhotic animals treated with adenosine or with adenosine aspartate (4 and 8 weeks).

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the compound known as adenosine (6-amino-ribofuranosyl purine) having the following formula (I): ADE OSIUA (I) Adenosine is a nucleoside widely distributed in nature, and is found in small amounts in almost all mammalian tissues. A second product derived from adenosine (ADO) can be synthesized, giving rise to an adenosine salt with the aspartic amino acid, which corresponds to the aspartate of the ADO (6-amino-ribofuranosyl) whose formula (II) is shown below and the reaction to obtain it is the following: ASPA RTATO AGENO S IKA Due to its non-polar condition, both ia 'denosina and su. salt, the ADO aspartate are easily permeable through cell membranes, which allows its enteral administration to be effective. Since there is practically no gastrointestinal catabolism for adenosine and for ADO aspartate, its absorption through the gastro-intestinal system allows it to reach the liver as a target organ, through the portal circulation. Therefore, its administration can be done both in non-enteric capsules and in tablets with a cover of the same nature. In this way, enteral administration of both adenosine and ADO aspartate could be highly effective in patients with impaired liver function to a lesser or greater degree. Based on the foregoing, the preferred way to apply the present invention is through the enteral administration of adenosine or ADO aspartate in a dose of 500 to 1,200 mg / day, for the treatment of liver diseases for a sufficient time to achieve the desired effect. The use of both nucleosides does not exclude the * administration of antivirals, vitamin and mineral supplements, diets rich in polyunsaturated fatty acids (for example: lecithins) or other control drugs for portal hypertension, hyperglycemia or those for palliative treatment of encephalopathy. hepatic origin. The preparation of a pharmaceutical composition that includes a therapeutically effective amount of adenosine and / or adenosine asparrate, can be carried out by employing standard techniques well known to those skilled in the art in combination with pharmaceutically acceptable carriers, such as example, of the degradable type. Adenosine is a natural product with a very active metabolism. However, ADO aspartate does not occur naturally in the metabolism of mammals. Hence, that its preparation represents a method as part of the cited invention.

The method consists in mixing equimolar concentrations of adenosine and aspartic acid dissolved in water under constant agitation, at room temperature and normal pressure. The final pH of the preparation will vary between 6.0 and 7.5. The time required for the formation of the compound is that in which a total solubility of the concentrations of the compounds is achieved separately, and its total lyophilization occurs. The formation of this salt can be easily checked by infrared spectroscopy and determine its melting point. These methods have shown that 'ADO aspartate has a melting point of 216-218 ° C and an infrared spectrum completely different from that of adenosine, whose melting point is 228-230 ° C, and pure aspartic is greater than 311 ° C. The above description and the following examples are intended to illustrate particular modes of carrying out the invention and should not be considered as limiting the scope of protection thereof. EXAMPLES OF THE INVENTION Example 1 The following example demonstrates the bioavailability of both adenosine and ADO aspartate in the liver of normal rats, as well as the protective effect of these molecules on mortality caused by chronic poisoning with carbon tetrachloride at lethal doses.

Male rats of the istar strain with a weight of 180 to 200 g (2 months of age) were used, which were maintained on the basis of a standard diet and with free access to water. The animals were subjected to 12-hour light-dark cycles. On the day of the experiment, a group of normal animals was administered 1 μCi of [14 C] adenosine or [14 C] ADA aspartate, to obtain an estimate of the nucleoside pharmacodynamics. These animals were sacrificed at 15, 30, 60 and 120 min., Taking samples of blood, liver and heart. The samples were deproteinized with 6% perchloric acid, the weight of the sample was quantified and the radioactivity present was counted, as a measure of the presence of adenosine or of adenosine aspartate or its derivatives. To determine the protective effect of the nucleosides, 3 experimental groups were prepared (20 animals per group): group A) received carbon tetrachloride through a gastric tube, in a single dose of 2.5 ml / kg of weight; group B) received carbon tetrachloride and was subsequently administered intraperitoneally 200 mg / kg of adenosine weight; group C) consisted of animals treated with carbon tetrachloride plus 50 mg / kg of aspartyl-ADO. Finally, the control group (n = 5) consisted of rats treated with the vehicle of both drugs (vegetable oil and saline). In the group of animals treated with carbon tetrachloride, the time of death was recorded, calculating the percentage of survival and taking liver samples for histological analysis (light microscopy). Reference is now made to the figures in which a brief explanation of the results obtained is provided, in which figure 1 summarizes the results of the pharmacokinetic distribution of adenosine (Ado) and adenosine aspartate (AspAdo) in the liver of normal rats and follow-up of the 14C mark (μmol) for a time in minutes, T (min) up to 2 hours after the administration of the drug. In the case of the liver concentration of adenosine, it is rapidly concentrated in the liver, after its enteral administration (15 min) and also decays rapidly after that time. Two hours after administration, the adenosine concentration drops to 20% of the initially reached concentration. In the case of animals treated with ADO aspartate, the increase in its concentration in the liver was not as high as in the case of adenosine, but its duration was much longer, suggesting its greater solubility and longer duration in liver tissue. . Figure 2 summarizes the results obtained from the percentage of survival (%) Sv against time in days, T (d), of the administration of adenosine (Ado) and of adenosine aspartate (AspAdo), in the case of fulminant toxic hepatitis (H). The animals that received only the toxic, quickly die in the first 24 hours, which means that after 48 hours the survival in this group is zero. The administration of adenosine in a single dose protects these animals spectacularly, obtaining up to 70% of survival after 3 days of treatment. The administration also in a single dose of ADO aspartate (four times less than adenosine) gave the same effect. Even, the protection obtained with the last compound was slightly higher than that achieved with adenosine.

EXAMPLE 2 The following example demonstrates the reversal effect of experimental cirrhosis, the normalization of liver function and the stimulation of hepatic regeneration in cirrhotic tissue, by the administration of both adenosine and ADO aspartate. Male rats were used, of the Wistar strain with an initial weight of 100 g, subjected to 12-hour cycles of light-dark, and free access to food and water. The animals received an induction treatment of cirrhosis, consisting of the administration of 25μl of carbon tetrachloride diluted in vegetable oil. A total of 30 doses (three times weekly) were administered intraperitoneally. During the induction process, body weight gain was recorded. At the end of the treatment (removal of carbon tetrachloride) the survival was greater than 85% and the animals showed clear histological evidence of cirrhotic alterations in samples taken from livers. Once the population of cirrhotic animals was completed, they were divided into three groups: Group A) cirrhotic rats that received only 10 to 20 doses of saline solution (three administrations per week); group B) cirrhotic rats that received 10 to 20 doses of 10 to 50 mg / kg of adenosine weight (4 and 8 weeks, respectively), and group C) that corresponded to the group of cirrhotic animals that received 20 doses of 50 mg / kg of ADO aspartate (8 weeks). Saline, adenosine and aspartyl-ADO were administered intraperitoneally. As controls, animals of the same age and weight were used, which only received saline intraperitoneally for the same period of time. After three days of the last administration of the aforementioned drugs, the animals underwent a moderate fast and were sacrificed under general anesthesia with sodium pentobarbital. Blood samples were taken from which the serum or plasma was separated, and the entire liver organ was removed and weighed. He also took the spleen and weighed it.

From the whole liver, samples of 1 to 2 grams of tissue were frozen for the determination of the amount of collagen, as a measure of the degree of liver fibrosis. With the rest of the liver, we proceeded to obtain subcellular fractions by differential centrifugation and use of gradients, of which the cytosolic fraction was used for the determination of thymidine kinase activity, as an indicator of the degree of hepatic proliferation. In serum, the levels of albumin and bilirubin were determined by spectrophotometric methods, as well as the activity of glutamic-pyruvic transaminase (TGP) and glutamic-oxaloacetic transaminase (GOT) enzymes. The collagen is extracted from the frozen tissue, as the fraction not soluble in a buffer solution of TRIS-HC1 (pH 7.4). The amount of collagen was determined by its content of hydroxyproline, as an amino acid characteristic of it. Thymidine kinase activity was carried out in the cytosolic fraction by a radiometric method, using thymidine labeled with 14C as substrate. The data are the mean ± standard error of at least 12 animals per group, and the statistical significance of the effects is determined by Analysis of Variance (ANOVA) and Student's t test. Reference is now made to the figures, in which figure 3 summarizes the results obtained in the amount of hepatic collagen CH in mg / g against the recovery time in weeks TR (S) (degree of fibrosis) in cirrhotic animals (Ci) treated with the vehicle, Control (C) or with the nucleosides. At the end of the treatment with carbon tetrachloride, the amount of collagen increased more than fivefold in the cirrhotic animal and, after treatment with the vehicle, no spontaneous reversion of the picture was found until more than two months of recovery. The animals that received adenosine (Ado) (10 doses in 4 weeks) showed a 35% decrease in the amount of hepatic collagen, and with 20 doses (8 weeks), the amount of collagen decreased up to 63% in the cirrhotic animals. The administration of adenosine aspartate (AspAdo) (20 doses in 8 weeks) promoted a decrease of up to 72% in the degree of fibrosis, evaluated by the amount of collagen; Figure 4 summarizes the effect of nucleosides on the liver function of cirrhotic animals in relation to the number of times over the control (V-Cj versus the recovery time in weeks TR (S).) The cirrhotic animal (Ci) presented high serum levels of TGP and GOT activities and the amount of bilirubin (B), while serum albumin (A) levels were significantly reduced at the end of the induction of cirrhosis. recovery in the cirrhotic animal, with the exception of a gradual increase in the amount of serum albumin.

The administration of both adenosine (Ado) and aspartyl-ADO (10 doses in 4 weeks) completely normalized the altered liver function of the cirrhotic liver, and figure 5 summarizes the effect of the adenosine nucleoside (Ado) and adenosine aspartate (AspAdo) on the regenerative capacity of the cirrhotic liver. At the end of the treatment, the thymidine kinase (TC) activity in relation to the number of times over the control (V-C), as an indicator of DNA synthesis, was found to be increased in the liver of the cirrhotic animal. However, this increase was rapidly depressed during the recovery phase, T-R (S) until not observed 2 months after the cirrogenic induction. The administration of 20 doses of adenosine and ADO aspartate (8 weeks) returned to the liver the ability to regenerate, coupled with the drastic reduction of fibrosis. Therefore, adenosine and its derived salt, ADO aspartate, were able to reverse a cirrhotic picture considered as irreversible, at the same time that normalized liver function and restored the liver capacity of cell proliferation. Likewise, these two nucleosides present an important antiviral activity in the decrease of the viral load in patients affected with viral hepatitis, by means of the analysis of amplification of the viral DNA by PCR of samples obtained from the patients treated with the compounds of this invention, which it is a standard technique well known to those skilled in the art. It is evident that other modifications and variations in accordance with what is set forth in the present invention can be carried out without departing from the spirit and scope thereof, as those skilled in the art will readily appreciate, the invention being protected by the following:

Claims (14)

1. CLAIMS 1. A method for the preparation of adenosine aspartate, characterized in that it comprises: reacting the adenosine compound of the formula I with aspartic acid; dissolved in water with constant agitation at room temperature and normal pressure; with a final pH of between about 6.0 to 7.5 during the time required for the formation of the adenosine aspartate of formula II, in which the total solubility of the reactants is achieved, followed by a lyophilization step.
2. 2. The method according to claim 1, wherein the adenosine compound of the formula I is 6-amino-ribofuranosyl purine.
3. 3. The method according to claim 1, "wherein the adenosine asparate of the formula II, is the 6-amino-ribofuranosyl.
4. 4. The adenosine aspartate of formula II, obtained from the method of claim 1, characterized in that it has a melting point of 216 to 218 ° C.
5. 5. The adenosine aspartate according to claim 4, characterized in that it also comprises a greater bioavailability and is rapidly metabolizable for the treatment of fibrosing liver diseases such as cirrhosis and chronic hepatitis.
6. 6. A pharmaceutical composition comprising a therapeutically effective amount of adenosine and / or adenosine aspartate in combination with a pharmaceutically acceptable carrier of the degradable type for the treatment of fibrosing liver diseases.
7. 7. The use of a therapeutically effective amount of the adenosine compound of the formula I and / or of the adenosine aspartate of the formula II, for the preparation of a "medicament for treating fibrotic disorders of the liver, such as cirrhosis leading to dysfunction liver disease of chronic encephalopathy.
8. 8. The use according to claim 7, characterized in that the adenosine compound of the formula I is 6-amino-ribofuranosyl purine.
9. 9. The use according to claim 7, characterized in that the adenosine asparate of the formula II is 6-amino-ribufuranosyl.
10. 10. The use according to claim 7, characterized in that the cirrhosis originates from any congenital, viral or alcohol consumption etiology, associated with secondary secondary pathology.
11. 11. The use according to claim 7, characterized in that adenosine and / or adenosine aspartate are administered predominantly enterally.
12. The use according to claim 11, characterized in that the adenosine and / or the adenosine aspartate are administered enterally in an effective dose of approximately 10 to 50 mg / kg of weight, with a pharmaceutically acceptable vehicle of the degradable type .
13. 13. The use according to claim 7, characterized in that it allows the reduction of hepatocellular necrosis, the arrest of fibrogenesis, the increase in the removal of scar tissue, the normalization of the hepatic cellular status, and the stimulation of the regeneration of a fibrotic liver, with profound alteration of liver function. The use according to claim 7, wherein the adenosine and / or adenosine aspartate is a substitute for liver transplantation or is a preparation for a successful achievement of said surgical procedure.