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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/05—Dipeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/401—Proline; Derivatives thereof, e.g. captopril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/06—Tripeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention refers to medical compositions and uses of said compositions for the treatment, alleviation and prophylaxis of conditions associated with cartilage impairment and pain related to it, or prophylaxis of artrose and rheumatoid arthritis and pain related to it.
• Embodiments of the invention include the use of a substance including 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 tripeptide 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 said 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 manufacture of a pharmaceutical preparation for the treatment or prophylaxis of a condition of inflammatory or non-inflammatory impairment of cartilage and pain related to above
• Further embodiments includes the use as stated above for the treatment or prophylaxis of cartilage impairment at conditions involving weight loss and/or impaired nutrition, or gastrectomy, partial gastrectomy or gastric banding.
• - fig. 1 is a diagram describing the effect of dietary aplha-ketoglutarat and gastrectomy on body weights of rats;
• - fig. 2 shows four transillumination photos of superior portion of cranium (calvaria) of experimental rats;
• - fig 3 is a diagram showing the area of lacunas as found on transillumination photos of calvaria of experimental rats.
• alpha-ketoglutaric acid or an alkali or alkaline earth metal salt thereof or a combination thereof is used.
• Preferably sodium alpha-ketoglutarate is used.
• a method for the treatment method for the treatment or prophylaxis of a condition of increased pain of at least one member selected from the group consisting of artrose in mammals, including man which method comprises administering to a subject in need for such treatment or prophylaxis of an effective pain amount of 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 tripeptide, dipeptides of glutamine and another amino acid, tripeptides of glutamine and other amino acids, dipeptides of glutamic acid and other amino acids, tripeptides of glutamic acid and other amino acids and pharmaceutically acceptable salts of said dipeptides and tripeptides, pharmaceutically accepted physical mixtures of alpha-ketoglutaric acid or a pharmaceutically acceptable salt thereof and at least one amino acid.
• alpha-ketoglutaric acid or an alkali or alkali or alkaline earth metal salt thereof or a combination thereof is administered.
• Most preferably sodium alpha-ketoglutarate is administered.
• the pharmaceutical preparations of the active principle or principles used in accordance with the present invention may be administered to a vertebrate, including mammals and birds, such as rodent, such as a mouse, rat, guinea pig, or a rabbit; a bird, such as a turkey, hen or chicken and other broilers and free going animals; a cow, a horse, a pig or piglet and other farm animals, a dog, a cat and other pets, and in particular humans. Administration may be performed in different ways depending what species of vertebrate to treat, on the condition of the vertebrate in the need of said methods, and the specific indication to treat.
• rodent such as a mouse, rat, guinea pig, or a rabbit
• a bird such as a turkey, hen or chicken and other broilers and free going animals
• a cow, a horse, a pig or piglet and other farm animals a dog, a cat and other pets, and in particular humans.
• Administration may be performed in different ways
• the administration is done as a food or feed supplement, such as a dietary supplement and/or a component in form of solid food and/or beverage. Further embodiments may be in suspensions or solutions, such as a beverage further described below. Also, the formats may be in capsules or tablets, such as chewable or soluble, e.g. effervescent tablets, as well as powder and other dry formats known to the skilled man in the art, such as pellets, such as micropellets, and grains.
• the administration may be as a parenteral, rectal or oral food or feed supplement, as revealed above. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
• the food and feed supplement may also be emulsified.
• the active therapeutic ingredient or ingredients may then be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient.
• excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof.
• the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH, buffering agents, which enhance the effectiveness of the active ingredient.
• Different formats of the parental food or feed supplement may be supplied, such as solid food, liquids or lyophilized or otherwise dried formulations. It may include diluents of various buffers (e.g., Tris-HCL, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatine to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethyleneglycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g.,Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the composition, complexation with metal ions, or incorporation of the material into or ontoparticulate preparations of
• 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 of these components are supplied in a dried form if the beverage is provided in a dry form.
• a beverage provided ready for consumption further comprises water.
• the final beverage solution may also have a controlled tonicity and acidity, e.g. as a buffered solution according to the general suggestions in the paragraph above.
• the pH is preferably in the range of about 2-5, and in particularly about 2-4, to prevent bacterial and fungal growth.
• a sterilised beverage may also be used, with a pH of about 6-8.
• the beverage may be supplied alone or in combination with one or more therapeutically effective composition.
• the pharmaceutical preparations as 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 active ingredient or ingredients in admixture with a pharmaceutically acceptable carrier and/or additives, such as diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers useful in the methods and use disclosed in the present invention.
• pharmaceutically acceptable carriers are well known to those skilled in the art and may include, but are not limited to, 0.01- 0.05M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may 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, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
• Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
• Amino acids forming part of amides with alpha-ketoglutaric acid or of dipeptides with glutamine or glutamic acid or tripeptides with glutamine and/or glutamic acid may be any of the amino acids occurring as components in peptides in nature. The same applies to the pharmaceutically accepted physical mixtures of alpha-ketoglutaric acid or salts thereof with at least one amino acid.
• the amino acid or acids is/are selected from the group consisting of arginine, ornithine, leucine, isoleucine and lysine.
• Said amino acids are preferably used in their L-configuration.
• Example as of amides of alpha-ketoglutaric acid with an amino acid or a di- or tripeptide include, but are not limited to, amides of alpha-ketoglutaric acid with an amino acid selected from the group consisting of glutamine, glutamic acid, arginine, ornithine, lysine, proline, isoleucine and leucine and amides of alpha- ketoglutaric acid with a dipeptide of glutamine and any of 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 connection with amides of alpha- keto
• Examples of physical mixtures of a-ketoglutaric acid or salts thereof with at least one amino acid includes, but are not limited to physical mixtures of at least one member selected from the group consisting of alpha-ketoglutaric acid and the sodium, potassium, calcium and magnesium salts thereof with any of glutamine, glutamic acid, arginine, ornithine, leucine, isoleucine, lysine and proline and any combinations of said amino acids.
• the molar ratio of alpha-ketoglutaric acid or salts thereof to amino acid or amino acids of said physical mixtures will in general be within the limits of from 1:0.01 to 1:2, preferably from 1:0.1 to 1:1.5 and most preferably from 1:0.2 to 1:1.0.
• the dosage to be administered will vary depending on the active principle or principles to be used, the condition to be treated, the age, sex, weight etc. of the patient to be treated but will generally be within the range from 1 to 1000 mg/kg body weight/day, or from 10 to 400mg/kg body weight and day, preferably from 10 to 100 mg/kg body weight/day.
• Gx 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 unclear whether Gx also adversely affects the epiphyseal plate.
• Dietary ⁇ -keto glutarate (AKG) is a precursor of hydroxyproline - the most abundant amino acid in the bone and cartilage pro-collagen. The aim of the studies was to highlight the effect of AKG on gastrectomy dependent bone/cartilage losses.
• Gastrectomy mainly affects trabecular bone and at times also cortical bone, inducing a pronounced effect of calvaria bone destruction. Reduction of cortical and trabecular bone mass after gastrectomy has been reported in both human sexes. Trabecular bone volume in tibia and femur is reduced by 60 % after 16 weeks postgastrectomy. Bone losses increase the risk of fractures of the hip, vertebrae and other sites among gastrectomy patients, which is a serious problem nowadays.
• bone loss in gastrectomized patients is not a result of dietary deficiencies (e.g. calcium) or lack of gastric acid or Vitamin D.
• the mechanism behind the gastrectomy- evoked osteopenia is still unknown. It is postulated, however, that the primary cause of osteoporoses is inefficient re- syntheses of bone collagen after its massive destruction by osteoclasts.
• the main component of bone pro-collagen is proline - the amino acids synthesize in the gastrointestinal tract from AKG via glutamate and via proline which in turn is converted in bone pro-collagen to hydroxyproline in the presence of AKG, vitamin C and Fe2+ .
• rats drank between 25 and 50 millilitres each day. In principle, it may 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 drink there is 0,36 g of AKG, which gives approximately 1 to 1,4 g of AKG per kg rat body weight and day. The rats in the placebo (control) group drank approximately 50 ml of placebo drink per day.
• Ketalar® 50 mg/kg; Parke- Davis, Morris Plains, NJ, U.S.A.
• Stresnil® 40 mg/kg; Janssen-Cilag Pharma, Vienna, Austria
• Analgesia was achieved by subcutaneous injection of Temgesic® (0.18 mg/kg; Schering-Plough, Kenilworth, NJ, U. S. A).
• Treatment was commenced of Sham+Placebo and Gx+Placebo groups with vehicle while Sham+AKG and Gx+AKG were treated with AKG.
• Gx rats were injected by the intramuscular route once every second week (beginning the first week after surgery) with 0.4 mg/kg of vitamin B 12 (Betolvex® 1 mg/ml, Dumex, Copenhagen, Denmark) to compensate for the loss of the intrinsic factor which is essential for the absorption of vitamin B 12 and 20 mg Fe 3+ /kg of ferric hydroxide poly maltose complex (Ferrum® 50 mg Fe 3+ mg/ml, Vifor (International) Inc., St. Gallen/Switzerland) as a supplement for the anticipated poor absorption of iron due to the loss of gastric acid. These supplementations were without effect on the body weight development of rats that had not undergone surgical procedures.
• vitamin B 12 Betolvex® 1 mg/ml, Dumex, Copenhagen, Denmark
• Fe 3+ /kg of ferric hydroxide poly maltose complex Ferum® 50 mg Fe 3+ mg/ml, Vifor (International) Inc., St. Gallen/Switzerland
• the calvaria were dissected out from each rat and cleaned of soft tissue by removing the periosteum carefully. Drying was avoided by covering each calvaria with gauze soaked in saline and storing them in an airtight container at +4°C until examination. Each calvarium was placed on a glass plate on top of a light source (commercial fluorescent tube), emitting light of constant intensity. The resulting transillumination images were photographed by the use of a camera connected to an operation microscope, magnification ⁇ l6. The images were subjected to histomorphometric computer analysis carried out by Image J v. 1.33 a. Percentage of bone lose (as observed area of lacunas) was estimated. Both the femora and tibiae were collected and stored in 70% ethanol until further analysis.
• Ethanol fixed left femora and tibiae were decalcified in 7% nitrogen acid for 48 hours.
• Distal femur and proximal tibia specimens (consisted of epiphysis with 8 mm part of metaphysis) were used for further histological processes. The specimens were immersed in paraffin. Longitudinal sections of femur and tibia specimens (6 ⁇ m thick) were cut by automatic microtome Microm HM 360. Twenty slices (with 20 ⁇ m interval after each 5) per 1 bone from 1 individual were cut. Slices were stained with hematoxylin/eosin under standard conditions. Microscopic images were taken from each stained slice.
• the pictures used to evaluate trabecular bone were taken using a Nikon Eclipse E800 - light microscope, magnification x 40 and Nikon D70 - digital photo camera.
• the microscopic images of sections of femur and tibia were subjected to histomorphometric computer analysis. Trabeculas were analyzed using ImageJ v. 1.33a.
• the pictures used to evaluate epiphyseal plate were made by means of the Nomarski contrast technique and collected by AXIOVERT 200 M equipped with an LSM 5 Pascal laser scanning head, Zeiss, magnification x 100, with argon laser wave length 514 nm. 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 laser scanning head, Zeiss, magnification x 100, with argon laser wave length 514 nm.
• Pictures of articular cartilage were evaluated by Zeiss LSM Image Examiner v. 3.1.0.99.
• trabeculas below epiphyseal plate were: trabecular bone volume (BV/TV %) measured to obtain characteristics of cancellous bone, and trabecular fractal dimensions (Box Counting Method).
• Parameters with regard to epiphyseal plate were: number of cartilage cells inside the ROI (Region Of Interest) consisting of Resting zone, Proliferative zone and Hypertrophic cartilage zone.
• BMD Bone Mineral Density
• BMC Bone Mineral Content
• the amount of cartilage collagen in Gx+ AKG group was similar to that in control (sham- operated) groups and was significantly higher in comparison to Gx+Placebo group (Table 2.).
• the aim of the experiment was to evaluate the effect of dietary ⁇ - ketoglutarate on bone loss caused by gastrectomy. Data obtained confirm that hypothesis. Indeed dietary AKG prevented bone and cartilage losses in gastrectomized rats. Our results are in agreement with recent experiments showing that AKG prevents the development of osteoporosis in ovariectomized rats and post-menopausal women.
• a protective effect of AKG on calvaria bone in gastrectomized rats was observed. Calvarias from Gx+AKG rats showed 20% less injury than those from Gx+Placebo rats.
• Gastrectomy has a strong destructive effect on the skeleton, causing osteopenia and arthropathy.
• AKG cannot totally stop these injuries but it definitely limited profound destructive gastrectomy-related changes in bones and cartilage and probably improved remodelling of the skeletal system.
• the implications of these observations can be important for clinical consideration in humans e.g. where partial gastrectomy is recommended for weight loss in obese patients. All these patients develop osteoporoses and arthropathy. Thus, one can speculate that dietary AKG for these patients can stop or limit these destructive bone changes.
• Table 1 Composition of AKG and placebo drinks.
• Fig. 1 Effect of dietary ⁇ -ketoglutarate and gastrectomy on body weights of rats.
• Control groups SHAM+PLAC, GX+PLAC
• Experimental groups SHAM+AKG, GX+AKG (SHAM - sham- operated rats, GX - gastrectomized rats).
• Fig. 2 Selected photos of calvaria of tested animals.
• Control groups SHAM+PLAC, GX+PLAC
• Experimental groups SHAM+AKG, GX+AKG (SHAM - sham-operated rats, GX - gastrectomized rats).
• Fig. 3 Effect of dietary ⁇ -ketoglutarate and gastrectomy on transillumination of calvaria.
• Control groups SHAM+PLAC, GX+PLAC

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