MX2008006203A - Medicament for use in connection with cartilage impairment - Google Patents

Abstract

Use of a substance for treating medical joint conditions,e.g.arthrosis, rheumatoid arthritis and cartilage impairment. The use includes the use of alpha-ketoglutaric acid, glutamine or glutamic acid, as well as salts, amides, di- or tripeptides of the mentioned substances.

Description

MEDICATION FOR USE IN RELATION TO THE DETERIORATION OF CARTILAGE Field of the Invention The present invention relates to medical compositions and uses of these compositions for the treatment, improvement and prophylaxis of conditions associated with deterioration of cartilage and pain related thereto, or prophylaxis of osteoarthritis and rheumatoid arthritis and pain related thereto. . Background of the Invention As many as one of three adults in the industrial world may currently suffer from chronic joint symptoms, or arthritis. The most common symptom, persistent joint pain, can appear as hip pain, knee pain, hand pain or wrist pain, as well as joint pain in other areas of the body. The symptoms can cause suffering in addition to the economic and painful losses when people are forced to leave their work or reduce work hours. Large sums are also spent on medical care. Obviously, there is a need for inexpensive solutions for the relief or cure of joint and arthritis symptoms.

REF .: 193066 Brief Description of the Invention The embodiments of the invention include the use of a substance that includes at least one member selected from the group consisting of alpha-ketoglutaric acid, glutamine, glutamic acid, and pharmaceutically acceptable salts of these acids, amides of alpha-ketoglutaric acid and an amino acid or a di- or tri-peptide, dipeptides of glutamine and another amino acid, tripeptides of glutamine and other amino acids, dipeptides of glutamine acid and other amino acids, tripeptides of glutamic acid and other amino acids and salts pharmaceutically acceptable of these dipeptides and tripeptides, pharmaceutically accepted physical mixtures of alpha-ketoglutaric acid or a pharmaceutically acceptable salt thereof and at least one amino acid for the preparation of a pharmaceutical preparation for the treatment or prophylaxis of an inflammatory or non-inflammatory deterioration condition of cartilage and pain related to previous. Additional modalities include the use as noted above for the treatment or prophylaxis of osteoarthritis and rheumatoid arthritis and pain related thereto. Additional modalities include the use as noted above for the treatment or prophylaxis of cartilage deterioration under conditions comprising weight loss and / or deficient feeding, or gastrectomy, partial gastrectomy or gastric narrowing with band. Additional modalities include use as noted above for the treatment or prophylaxis of cartilage deterioration in conditions comprising malnutrition. Additional modalities include use as noted above for the relief of pain associated with cartilage deterioration under the conditions mentioned above. Additional modalities include the use as noted above for the treatment or prophylaxis of osteoporosis related to gastrectomy. Brief Description of the Figures The present invention will be further explained in the following description with the aid of preferred embodiments, example studies and appended figures, of which: Figure 1. - Effect of dietary-ketoglutarate and gastrectomy on body weights of rats. Control groups: in False + PLAC, Gx + PLAC, Experimental groups: in FALSE + AKG, Gx + AKG (in FALSE.- rats operated in False, Gx.- rats with gastrectomy).

Figure 2.- Selected photos of cranial vaults of tested animals. Control groups: in FALSE + PLAC, Gx + PLAC, Experimental groups: in FALSE + AKG, GX + AKG (in FALSE.- rats operated in false, Gx.- rats with gastrectomy). Figure 3.- Effect of dietary α-ketoglutarate and gastrectomy in back-lighting of cranial vaults. Control groups: in FALSE + PLAC, Gx + PLAC, Experimental groups: in FALSE + AKG, Gx + AKG (in FALSE.- rats operated in false, Gx.- rats with gastrectomy). * p = 0.0288 Detailed Description of the Invention This way, according to one aspect of the present invention, the novel use of at least one member selected from the group consisting of alpha-ketoglutaric acid, glutamine, glutamic acid and pharmaceutically acceptable salts of these acids, alpha-ketoglutaric acid amides is provided. and an amino acid or a di- or tri-peptide, dipeptides of glutamine and another amino acid, tripeptides of glutamine and other amino acids, dipeptides of glutamine acid and other amino acids, tripeptides of glutamic acid and other amino acids and pharmaceutically acceptable salts of these dipeptides and tripeptides, pharmaceutically accepted physical mixtures of alpha-ketoglutaric acid or a pharmaceutically acceptable salt thereof and at least one amino acid for the preparation of a pharmaceutical preparation for the treatment or prophylaxis of an arthrosis, rheumatoid arthritis and cartilage destruction and related pain condition to the above disorders. According to a preferred embodiment of the invention, alpha-ketoglutaric acid or an alkaline or alkaline earth metal salt thereof or a combination thereof is used. Preferably, sodium alpha-ketoglutarate is used. According to another aspect of the present invention, there is provided a method for the treatment or prophylaxis of an increased pain condition of at least one member selected from the group consisting of osteoarthritis in mammals, including man, a method comprising administering to a subject in need of this treatment or prophylaxis an effective amount for pain of at least one member selected from the group consisting of alpha-ketoglutaric acid, glutamine, glutamic acid and pharmaceutically acceptable salts of these acids, alpha-ketoglutaric acid amides and an amino acid or a di- or tri-peptide, dipeptides of glutamine and other amino acid, tripeptides of glutamine and other amino acids, dipeptides of glutamine acid and other amino acids, tripeptides of glutamic acid and other amino acids and pharmaceutically acceptable salts of these dipeptides and tripeptides, mixtures pharmaceutically acceptable substances of alpha-ketoglutaric acid or a pharmaceutically acceptable salt thereof and at least one amino acid. According to preferred embodiments of these aspects, alpha-ketoglutaric acid or an alkaline or alkaline earth metal salt thereof or a combination thereof is administered. More preferably, sodium alpha-ketoglutarate is administered. Pharmaceutical preparations of the active ingredient (s) used in accordance with the present invention may be administered to a vertebrate, including mammals and birds, such as a rodent, such as a mouse, rat, guinea pig, or rabbit.; a bird, such as a turkey, chicken or chicken and other animals selected for rapid growth and other animals that roam freely; a cow, a horse, a pig or piglet and other farm animals, a dog, a cat and other pets, and in particular humans. The administration can be carried out in different ways depending on which species of vertebrate is concerned, the condition of the vertebrate in need of these methods, and the specific indication in question. In one embodiment, the administration is made as a food or food supplement, such as a dietary supplement and / or a component in the form of solid food and / or beverage. Additional embodiments may be in suspensions or solutions, such as a beverage described further below. Also, the formats can be in capsules or tablets, such as chewable or soluble, for example, effervescent tablets, as well as powders and dry formats known to the person skilled in the art, such as granules, such as microgranules, and grains. The administration can be parenteral, rectal or oral food or oral food supplement, as disclosed above. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, fixed or lactated Ringer's oils. The food and food supplement can also be emulsified. The active therapeutic ingredient or ingredients can then be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH, buffering agents, which improve the effectiveness of the active ingredient. Different formats of the parenteral food or food supplement, such as solid food, liquids or formulations lyophilized or otherwise dried can be provided. They may include diluents of various buffers (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, salts of bile acids), solubilizing agents (eg, glycerol, polyethylene glycerol), antioxidants (eg, ascorbic acid, sodium metabisulfite), preservatives (eg, thimerosal, benzyl alcohol, parabens), bulk substances or tonicity modifiers (for example, lactose, mannitol), covalent attachment of the polymers such as polyethylene glycol to the composition, formation of complexes with metal ions, or incorporation of the material in or on preparations of particles of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, etc., or on liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. In one embodiment, the food or food supplement is administered in the form of a beverage, or a dry composition thereof, in any of the methods according to the invention. The beverage comprises an effective amount of the active ingredient or ingredients thereof, together with a nutritionally acceptable water soluble carrier, such as minerals, vitamins, carbohydrates, fat and proteins. All these components are supplied in a dry form if the beverage is provided in a dry form. A beverage provided ready for consumption also comprises water. The final beverage solution may also have a controlled acidity tonicity, for example, as a buffered solution according to the general suggestions in the previous paragraph. The pH is preferably in the range of about 2-5, and in particular about 2-4, to prevent bacterial and fungal growth. You can also use a sterilized drink, with a pH of approximately 6-8. The beverage may be administered alone or in combination with one or more therapeutically effective compositions. According to a further embodiment, the pharmaceutical preparations as a drug for oral and rectal use may be in the form of tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, aqueous solutions and the like comprising the ingredient or ingredients active in admixture with a carrier and / or pharmaceutically acceptable additives, such as diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers useful in the methods and use described in the present invention. Additionally, as used herein, "pharmaceutically acceptable carriers" as is well known to those skilled in the art and may include, but are not limited to, phosphate buffer at 0.01-0.05 M or 0.8% saline. Additionally, these pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, solutions, emulsions or alcoholic / aqueous suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, fixed or lactated Ringer's oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. The amino acids that are part of amides with alpha-ketoglutaric acid or of dipeptides with glutamine or glutamic acid or tripeptides with glutamine and / or glutamic acid can be any of the amino acids that occur as components in peptides in nature. The same applies to pharmaceutically accepted physical mixtures of alpha-ketoglutaric acid or salts thereof with at least one amino acid. Preferably, the amino acid or amino acids are selected from the group consisting of arginine, ornithine, leucine, isoleucine and lysine. These amino acids are preferably used in their L configuration. Examples of alpha-ketoglutaric acid amides with an amino acid or a di- or tri-peptide include, but are not limited to, alpha-ketoglutaric acid amides with a selected amino acid from the group consisting of glutamine, glutamic acid, arginine, ornithine, lysine, proline, isoleucine and leucine and alpha-ketoglutaric acid amides with a dipeptide of glutamine and either glutamic acid, arginine, ornithine, lysine, proline, isoleucine and leucine and with a dipeptide of glutamic acid and any of arginine, ornithine, lysine, proline, isoleucine and leucine. Examples of di- and peptides of glutamine and glutamic acid with other amino acids include those mentioned above in conjunction with alpha-ketoglutaric acid amides with di- or tri-peptides. Examples of physical mixtures of an alpha-ketoglutaric acid or salts thereof with at least one amino acid include, but are not limited to, physical mixtures of at least one member selected from the group consisting of alpha-ketoglutaric acid and the sodium salts. , potassium, calcium and magnesium thereof with any of glutamine, glutamic acid, arginine, ornithine, leucine, isoleucine, lysine and proline and any combination of these amino acids. The molar ratio of alpha-ketoglutaric acid or salts thereof to the amino acid or amino acids of these physical mixtures will generally be within the range of from 1: 0.01 to 1: 2, preferably from 1: 0.1 to 1: 1.5 and so more preferred from 1: 0.2 to 1: 1.0. The dose that is administered will vary depending on the principle or active ingredients that are going to be used, the condition being treated, the age, sex, weight, etc., of the patient in question but in general it will be within the range of 1 to 1000 mg / kg of body weight / day, or from 10 to 400 mg / kg of body weight and day, preferably from 10 to 100 mg / kg of body weight / day. The invention will now be further illustrated by way of example which should not be construed as limiting the scope of the invention. Example Background: Surgical removal of the stomach (gastrectomy, Gx) leads to osteoporosis in animals and in humans. Gastrectomy mainly affects the structure of trabecular bone. It is not clear if Gx also adversely affects the epiphyseal plaque. Dietary α-ketoglutarate (AKG) is a precursor of hydroxyproline, the most abundant amino acid in bone and pro-collagen in cartilage. The purpose of the studies was to highlight the effect of AKG on cartilage / bone loss dependent on gastrectomy. Methods: 40 female Sprague-Dawley rats were used. Twenty rats underwent gastrectomy and were divided into 2 groups: Gx + AKG and Gx + Placebo. Another 20 rats were operated on false and divided between 2 other groups: False + AKG and False + placebo. After 8 weeks, the animals were sacrificed and the cranial, femoral and tibial vaults were collected. Bone mass density (BMD) and bone mineral concentration (BMC) were estimated in right femoral and right tibial bones, and histomorphometries of left bones were estimated. Cranial vault backlighting measurements were also performed. Results: Dietary α-ketoglutarate revealed a strong protective effect in bone losses of cranial vaults of rats with gastrectomy. The AKG exhibits a strong anti-destructive effect on cells of the epiphyseal plate, the volume of the trabecular bone and in the shape of the trabeculae of the rats with gastrectomy. Conclusions: AKG minimizes the destruction of bone and cartilage developed after stomach resection in rats. Surgical removal of the stomach leads to osteopenia and arthritis in humans, the rat and other experimental animals. Gastrectomy is associated with osteopenia in humans. Gastric dysfunctions can also contribute to the development of osteoporosis in old age. Therefore, most studies regarding bone disease treat patients after gastric resection. The gastrectomy mainly affects the trabecular bone and sometimes also the cortical bone, inducing a pronounced effect of destruction of bone in the cranial vaults. The reduction of cortical and trabecular bone mass after gastrectomy has been reported in both human sexes. The trabecular bone volume in the tibia and femur is reduced by 60% after 16 weeks after the gastrectomy. Bone loss increases the risk of fractures of the hip, vertebrae and other sites among patients with gastrectomy, which is currently a serious problem. It is postulated that bone loss in patients with gastrectomy is not the result of dietary deficiencies (eg, calcium) or lack of gastric acid or Vitamin D. The mechanism behind osteopenia caused by gastrectomy is still unknown. However, it is postulated that the main cause of osteoporosis is the inefficient re-synthesis of bone collagen after its massive destruction by osteoclasts. The main component of pro-collagen bone is proline, the amino acids synthesized in the gastrointestinal tract from AKG by glutamate and by proline which in turn is converted to bone pro-collagen to hydroxyproline in the presence of AKG, vitamin C and Fe2 +. Recently it was shown that AKG has been effective in the prevention of bone loss in rats with ovariectomy, and denervated bones in turkeys. In consideration of all the above, the main purpose of the studies was to investigate whether dietary AKG can prevent bone and cartilage losses in rats with gastrectomy. Animals and Surgical Procedures Forty female Sprague-Dawley rats, 10 weeks old (220-230 g) were housed, in Macrolon ™ cages (2 rats in each cage) and given a diet of standard rat food pellets (Lacta in, Vadstena, Sweden) and vehicle or AKG ad libi tum dissolved in water (Table 1). The study lasted 8 weeks. The rats were weighted every week. The rats drank between 25 and 50 milliliters each day. In principle, it can be assumed that rats drink between 10 and 20% of body weight. The rats of the AKG group drank approximately 25 ml of AKG drink per day. In 25 ml of beverage there is 0.36 g of AKG, which gives about 1 to 1.4 g of AKG per kg of body weight of rat per day. The rats in the placebo group (control) drank approximately 50 ml of placebo drink per day. Surgery Twenty rats were gastrectomized and divided into 2 groups: Bx + AKG and Gx + Placebo (10 rats in each group). The glandular portion of the stomach (ie, the acid producing part, fundic gland and the pyloric antrum) was excised after which the non-glandular part (ante-stomach) was joined with the duodenum from end to end. We operated on false 20 rats and were divided into 2 groups: False + AKG and False + placebo (10 rats in each group). The false operation involved a midline abdominal incision, manipulation of the stomach and closure of the incision. Anesthesia was achieved by subcutaneous injection of Ketalar ™ (50 mg / kg; Parke-Davis, Morris Plains, NJ, USA) and Stresnil ^ (40 mg / kg, Janssen-Cilag Pharma, Vienna, Austria). Analgesia was achieved by subcutaneous injection of Temgesic1 (0.18 mg / kg, Schering-Ploug, Kenilworth, NJ, USA). The treatment of the False + Placebo and Gx + Placebo groups with vehicle was started while they were treated in Faso + AKG and Gx + AKG with AKG. Gx rats were treated by the intramuscular route once every second week (starting the first week after surgery) with 0.4 mg / kg of vitamin B12 (Betolvex1 1 mg / ml, Dumex, Copenhagen, Denmark) to compensate for the loss of intrinsic factor that is essential for the absorption of vitamin B 2 and .0 mg of Fe g of poly-maltose complex with ferric hydroxide (Ferrum 50 mg Fe3 + mg / ml, Vifor (International) Inc., St. Gallen / Switzerland ) as a supplement for poor iron premature absorption due to the loss of gastric acid. These implementations were without effect on the body weight development of the rats that have not undergone surgical procedures. During the experiment, 8 animals died. The final number of animals (n) was 7 in Faso + Placebo, 10 in False + AKG, 8 in Gx + Placebo and 7 in Gx + AKG. All rats were sacrificed by bleeding from the abdominal aorta under anesthesia as mentioned above. Studies were approved by the local Animal Welfare Committee, Lund, Sweden. Tissue Collection and Analysis The cranial vaults were excised from each rat and cleaned of soft tissue by carefully removing the periosteum. Drying was avoided by covering each cranial vault with gauze dampened in saline solution and by storing it in an airtight container at + 4 ° C until the examination. Each cranial vault was placed on a glass plate on top of a light source (commercial fluorescent tube), which emits light of constant intensity. The resulting backlighting images were photographed by the use of a camera connected to a microscope in operation, magnification? 16. The images were subjected to histomorphometric analysis by computer carried out by Image J v. 1.33a. The percentage of bone loss (as observed area of lagoons) was estimated. Both the femurs and the tibias were collected and stored in 70% ethanol until further analysis. The right femurs and tibias were subjected to PIXIMUSMR analysis, which gives the BMD in g / cm2 and the BMC in g / cm3. The left femurs and tibias fixed in ethanol were decalcified in 7% acid nitrogen for 48 hours. Specimens from the distant femur and proximal tibia (consisting of epiphysis with part of 8 mm metaphysis) were used for additional histological processes. The specimens were immersed in paraffin. Longitudinal sections of the femur and tibia specimens (6 um thick) were cut by the Micron HM 360 automatic microtome. Twenty sections (20 μm interval after each 5) were performed per 1 bone of 1 individual. The sections were stained with hematoxylin / eosin under normal conditions. Microscopic images of each stained cut were taken. The images used to evaluate the trabecular bone were taken using a Nikon Eclipse E800 light microscope, magnification x 40 and a Nikon D70 digital camera. The microscopic images of the sections of the femurs and tibias were subjected to histophometric analysis by computer. The trabeculae were analyzed using Imagej v. 1.33a. The images used to evaluate the epiphyseal plate were made by means of the Nomarski contrast technique and were collected by AXIOVERT 200 M equipped with a laser scan head LSM 5 Pascal, Zeiss, magnification x 100, with argon laser wavelength of 514 nm. The epiphyseal plate was analyzed using Analysis v. 3.0. Articular cartilage images were captured using fluorescent mode of AXIOVERT 200 M equipped with an LSM 5 Pascal, Zeiss laser scan head, magnification x 100, with argon laser wavelength of 514 nm. Articular cartilage images were evaluated by the image examiner Zeiss LSM v. 3.1.0.99. The parameters considered with respect to the trabeculae below the epiphyseal plate were: trabecular bone volume (% BV / TV) measured to obtain cancellous bone characteristics, and trabecular fractal dimensions (box counting method). The parameters with respect to the epiphyseal plate were: number of cartilage cells within the ROI (region of interest) consisting of the resting zone, proliferative zone and hypertrophic zone of cartilage. Estimation of relative collagen content of articular cartilage was made by measuring fluorescence intensity of collagen stained with eosin in ROI of random choice (the same area for each cut, 6 circles each of 83 μm in diameter, together with the articular cartilage ), with Pascal LSM 5 laser scan head detector, 12-bit gray level, as a measurement scale. Measurements were taken in exactly the same normal conditions for each cut. Statistics Data were compared with the unidirectional analysis of variance (ANOVA), Student's t-test, and was considered p <0.05 statistically significant. Results At the end of the experiment, the body mass of the surgically treated animals was 8% lower than those operated in false. There were no statistically significant differences between the groups (Figure 1).

Backlighting of cranial vaults Backlighting of the cranial vaults showed significant growth in percentage of bone gaps in the Gx + Placebo and Gx + AKG rats compared to the rats in False + Placebo and in False + AKG (Figure 2 ). Gx + AKG rats also exhibit a significantly lower percentage of gaps compared to the Gx + Placebo group (* p = 0.031) (Figure 3). The differences between False + Placebo and False + AKG were not statistically significant. Bone Mineral Density (BMD) and Bone Mineral Content (BMC) in Femur and Tibia The BMD and BMC were lower in the Gx + Placebo and Gx + AKG rats compared to the False + Placebo and Faso + AKG rats (data not shown). However, the BMD in Gx + AKG tended to be greater than in the Gx + Placebo group (p = 0.19). Histomorfornetry Analysis of Articular Cartilage The amount of cartilage collagen in the group Gx + AKG was similar to that in control groups (operated in false) and was significantly higher in comparison to the Gx + Placebo group (Table 2). Epiphyseal Plate Analysis Quantitative estimation of epiphyseal growth plate cells showed an increase in the number of cells in the Gx + AKG group (both in the femur and in the tibia) compared to Gx + Placebo. In addition, the number of cartilage cells in the Gx + AKG group was significantly higher than in both false groups (Tables 3, 4). Trabecular Bone Volume Trabecular bone volume decreased in rats Gx + Placebo and Gx + AKG compared to rats in False + Placebo and in False + AKG. However, the reduction of the area of the trabeculae in Gx + AKG was lower than in the group of Gx + Placebo (Tables 5, 6). Fractal Dimension of Bone Trabeculae The fractal dimension in Gx + AKG was similar to the control group and was greater than in Gx + Placebo (Tables 7, 8).

The purpose of the experiment was to evaluate the effect of dietary α-ketoglutarate on bone loss caused by gastrectomy. The data obtained confirm this hypothesis. In fact, dietary AKG prevented bone and cartilage losses in rats with gastrectomy. The present results are in accordance with recent experiments showing that AKG prevents the development of osteoporosis in rats with oophorectomy and post-menopausal women. Gastrectomy caused loss of cartilage and cartilage collagen cells in rats with Gx + Placebo but not in Gx + AKG. 22% more cartilage cells were confirmed in Gx + AKG than in the Gx + Placebo group. This indicates that AKG was effective in preventing the loss of cartilage cells in rats with gastrectomy. The analysis revealed a protective effect of AKG on bone and cartilage collagen. The amount of collagen in the group with Gx + AKG was within the range of control groups for the experiment and was more than 18% higher than in rats with Gx + Placebo. A protective effect of AKG was observed in the bone of cranial vaults in rats with gastrectomy. The cranial vaults of the rats with Gx + AKG showed 20% less injury than those of the rats with Gx + Placebo. The values of BMD and BMC showed that gastrectomy caused osteopenia in the rats with Gx + Placebo and Gx + AKG that is in agreement with other experiments. However, using more sensitive methods, it was shown that AKG is possibly effective in the prevention of osteopenia in rats with GX.

In addition, the trabecular bone volume examined showed 38% less decrease in rats with Gx + AKG compared to animals with Gx + Placebo. In addition, the fractal dimension of the trabeculae in the group with Gx + AKG showed almost the same level as in the groups operated in false. In this way, a-ketoglutarate has a strong influence on the remodeling of the structure of the bone trabeculae. Gastrectomy has a strong destructive effect on the skeleton, causing osteopenia and arthropathy. The AKG can not completely stop these injuries but definitely limited deep destructive changes related to gastrectomy in bones and cartilage and probably improved the remodeling of the skeletal system. The implications of these observations may be important for clinical consideration in humans, for example, where partial gastrectomy is recommended for weight loss in obese patients. All these patients developed osteoporosis and arthropathy. In this way, it can be speculated that the dietary AKG for these patients can stop or limit these destructive bone changes.

Table 1.- Composition of drinks with AKG and placebo To achieve the same pH level in each solution, the placebo drink was triturated with 0.1 M HCl at pH 4.6 (the pH level of the AKG drink).

Table 2. - Effect of AKG and gastrectomy on relative content of collagen of articular cartilage A different letter given with a result in a column describes significant difference when p < 0.05 n = 7 in Gx + AKG, n = 8 in Gx + Placebo, n = 10 in False + AKG, n = 7 in False + Placebo Table 3.- Effect of AKG and gastrectomy in the number of epiphyseal plate chondrocytes of femurs A different letter given with a result in a column describes significant difference when p < 0.05 n = 7 in Gx + AKG, n = 8 in Gx + Placebo, n = 10 in False + AKG, n = 7 in False + Placebo Table 4.- Effect of AKG and gastrectomy on the number of epiphyseal platelet chondrocytes Treatment Number of cells / mm2 SD Gx + AKG 2470a 470 Gx + Placebo 1950b 330 In False + AKG 1840b 410 In False + Placebo 2110b 340 One letter different given with a result in a column describes significant difference when p < 0.05 n = 7 in Gx + AKG, n = 8 in Gx + Placebo, n = 10 in False + AKG, n = 7 in False + Placebo Table 5.- Effect of a-ketoglutarate astrectomy in A different letter given with a result in a column describes significant difference when p < 0.05 n = 7 in Gx + AKG, n = 8 in Gx + Placebo, n = 10 in False + AKG, n = 7 in False + Placebo Table 6.- Effect of a-ketoglutarate and gastrectomy in A different letter given with a result in a column describes significant difference when p < 0.05 n = 7 in Gx + AKG, n = 8 in Gx + Placebo, n = 10 in False + AKG, n = 7 in False + Placebo Table 7.- Effect of a-ketoglutarate and gastrectomy in fractal dimensions trabeculae of femurs A different letter given with a result in a column describes significant difference when p < 0.05 n = 7 in Gx + AKG, n = 8 in Gx + Placebo, n = 10 in False + AKG, n = 7 in False + Placebo Table 8. - Effect of a-ketoglutarate and gastrectomy in A different letter given with a result in a column describes significant difference when p < 0.05 n = 7 in Gx + AKG, n = 8 in Gx + Placebo, n = 10 in False + AKG, n = 7 in False + Placebo It is noted that in relation to this date, the best method known to the applicant for to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (11)

1. Claims Having described the invention as above, the content of the following claims is claimed as property: 1. Use of alpha-ketoglutaric acid or pharmaceutically acceptable salt of alpha-ketoglutaric acid for the preparation of a pharmaceutical preparation for the treatment or prophylaxis of deterioration of cartilage under conditions comprising weight loss and / or impaired feeding; malnutrition; gastrectomy, partial gastrectomy or gastric narrowing with band.
2. 2. Use according to claim 1, wherein the alpha-ketoglutaric acid or the pharmaceutically acceptable salt of alpha-ketoglutaric acid is a pharmaceutically acceptable physical mixture with at least one amino acid.
3. 3. Use according to claim 2, wherein the amino acid is selected from: glutamine, glutamic acid, arginine, ornithine, leucine, isoleucine, lysine, proline and combinations thereof.
4. 4. Use according to claims 1-3, wherein the pharmaceutically acceptable salt of alpha-ketoglutaric acid is an alkaline salt or an alkaline earth metal salt or a combination thereof.
5. 5. Use according to claims 1-4, wherein the pharmaceutically acceptable salt of alpha-ketoglutaric acid is sodium alpha-ketoglutarate.
6. 6. Use of alpha-ketoglutaric acid amides and an amino acid, a dipeptide or a tripeptide, for the preparation of a pharmaceutical preparation for the treatment or prophylaxis of cartilage deterioration under conditions comprising weight loss and / or deficient feeding; malnutrition; gastrectomy, partial gastrectomy or gastric narrowing with band.
7. 7. Use according to claim 6, wherein the amino acid forming the amide with alpha-ketoglutaric acid is selected from: glutamine, glutamic acid, arginine, ornithine, lysine, proline, isoleucine and leucine.
8. 8. Use according to claim 6, wherein the dipeptide forming the amide. with alpha-ketoglutaric acid is a dipeptide of glutamine and any of: glutamic acid, arginine, ornithine, lysine, proline, isoleucine and leucine.
9. 9. Use according to claims 1-8, wherein the dose given to a patient is in the range of 1 to 1000 mg / kg of body weight / day of the substance.
10. 10. Use according to claims 1-8, wherein the dose given to a patient is in the range of 10 to 400 mg / kg of body weight / day of the substance.
11. 11. Use according to claims 1-8, wherein the dose given to patients is in the range of 10 to 100 mg / kg of body weight / day of the substance.