Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
  • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones

Definitions

• the present invention is related to a novel method for the treatment of several bone affecting diseases, especially osteoporosis, which are characterized by loss of bone mass.
• bone formation which is associated with the number and activity of osteoblasts, that is cells associated with the production of bone in the organism
• bone loss which is associated with the number and activity of osteoclasts, that is cells associated with the absorption and removal of bone
• osteoporosis can be mentioned, Paget's disease of bone, hyperparathyroidism and related disorders, and several malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia.
• osteoporosis bone formation as well as bone resorption are disturbed, resulting in loss of bone tissue, decreased bone mass, and bone fragility. Osteoporosis predominantly affects the elderly, but also other groups such as po ⁇ _menopausal women, where an estrogen deficit is believed re be a significant etiological factor, and immobilized patients. At this point it is not possible to clear up the whole picture of the disease mechanism and estimate which is the primary cause of osteoporosis. However, about 25% of osteoporotic females belong to what is called "rapid bone losers" and at least in those patients the bone resorption rate is probably increased.
• Landry and Fleisch showed in immobilization induced osteoporosis that bone resorption rate was accelerated, (Landry, M. and Fleisch, H.: The influence of immobilization on bone formation as evaluated the incorporation of tetracyclines. J. Bone Joint Surg. 46B:764, 1964).
• osteoporosis comprise fractures, especially hip fractures, but also vertebral fractures and fractures of the proximal radius, and complication of such fractures.
• the present methods for the treatment of osteoporosis include exercise? administration of estrogen, especially for postmenopausal women; and consumption of calcium or calcium containing material such as milk. Calcitonin, a hormone associated with calcium metabolism, has also been used in the treatment of osteoporosis.
• malignant tumors are known to be associated by hypercalcemia which is due to increased osteoclastic activity. This is a common complication for instance in the case of breast cancer and prcstats cancer which are both one of the most common malignant tumors. Hypercalcemia is due to both systemic and local factors .
• Some malignant cells are known to secrete agents which stimulate bone resorption (Sato, K,; Fujii, Y., Kachivehi, T., Kasono, K., Shizume, K. : Production of interleukin 1 alpha (IL-1 ⁇ )-like activity and colony stimulating activity by clonal sguanous cell carcinomas derived from patients with hypercalcemia and leucocytosis. In: Calcium Regulation and Bone Metabolism Vol. 9 (eds. D.V. Cohu, T.J. Martin, P.J. Meunier), 1986).
• Paget's disease (or osteitis deformans) of bone is a disease of unknown etiology where bone resorption and remodelling are increased leading sometimes even to the fractures of affected bone. Bone pain is the main indication of treatment in these patients. In these patients there is highly elevated local osteoclastic bone destruction. The incidence of osteitis deformans is vey low in Scandinavian countries. In England it has been estimated to be present in 3-4% of population on the basis of autopsy studies (Anderson's Textbook of Pathology 1986). It is very rare in patients under 40 years. Calcitonin and diphosphonates are also used in the treatment of Paget's disease.
• H 2 -receptor-blocking agents are useful as prophylactic and therapeutic agents for the treatment of osteoporosis; Paget's disease of bone; hyperparathyroidism, both primary and secondary; malignant neoplasms where tumor cells are producing osteoclast- activating factors and cause hypercalcinemia; immobilization-induced osteoporosis; parodontal diseases; and prostetic and implant-related bone losses.
• H 2 -receptor-blocking agents examples include:
• the preferred H 2 -blocking agents are cimetidine and ranitidine.
• the invention relates to
• a pharmaceutical preparation for use in the prophylactic and therapeutic treatment of each of the ailments above comprising a H 2 -receptor-blocking agent as active ingredient
• a H 2 -receptor-blocking agent for use in the manufacture of a medicament for the prophylactic and therapeutic treatment of each of the ailments above.
• a method for improving the healing rate of bone fractures by administering to a host in need thereof of an effective amount of a H 2 -receptor -blocking agent.
• Sprague-Dawley male rats (Alab, Sweden) weighing 175-200 g before the tests were used. They obtained a standard diet consisting of rat feed pellets (Alab, Swiss, Sweden) and tap water.
• Nine rats were given ranitidine (Hassle, Sweden) 1700 ⁇ mol/kg x day, approximately 600 mg/kg body weight per day) via osmotic mini pumps (Alzet 2ML2) which had been implanted subcutaneously.
• the rats were treated during 26 days and mini pumps were exchanged after 14 days. The pumps were placed under the abdominal skin. Seven rats were used as untreated controls.
• Serum was prepared at the blood tapping from each rat and gastrin was determined by radioimmunoanalysis (Stadil, F. & Rehfeld, J.F. (1973) Determination of gastrin in Serum. An evaluation of the reliability of a radioimmunoassay. Scan. J. Gastroent. 8, 101-112; Hakansson, R. , Kroesen, J.H. Liedberg, G., Oscarson, J., Rehfeld, J.E.. & Stadil, F. (1974) Correlation between serum gastrin concentration and rat stomach histidine decarboxylase activity, J. Physiol. 243, 483-498).
• Gastrectomia was prepared by resection of the stomach followed by suturation of eosophagus and duodenum end to end. Operated animals were allowed to recover for one week before treatment with the test substance, as has been described in "Pharmacological tests". The test results are given in Fig. 1 and Fig. 2.
• Fig.l shows the concentration of gastrin expressed as picogram/ml serum with untreated control rats (average of 7 rats, and with ranitidir-e-treated rats (average of 9 rats) after treatment for 26 days.
• Fig. 2 shows the amount of radioactive calcium which has been incorporated into the skeleton (radius respectively sternum) expressed in cpm/mg bone ashes.
• E shows the average of 7 control rats
• F shows the average of 9 ranitidine-treated rats
• G shows the average of 7 control rats
• H shows the average of 9 ranitidine-treated rats.
• the continuous lines represent the average of given number of rats and the dashed lines represent the standard error of the average value.
• Ih ⁇ pharmaceutical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier.
• the carrier may be in the form of a solid, semi- solid or liquid diluent, or a capsule.
• These pharmaceutical preparations are a further object of the invention.
• the amount of active compounds is between 0.1-95 % by weight of the preparation, between 0.2-20 % by weight in preparations for parenteral use and between 1 and 50 % by weight in preparations for oral administration.
• the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 2000 mg per day of active substance.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Physical Education & Sports Medicine (AREA)
• Diabetes (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Rheumatology (AREA)
• Endocrinology (AREA)
• Nutrition Science (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1987
  • 1987-11-13 SE SE8704436A patent/SE8704436D0/xx unknown
• 1988
  • 1988-10-27 AU AU27203/88A patent/AU2720388A/en not_active Withdrawn
  • 1988-10-27 JP JP63509275A patent/JPH02502188A/ja active Pending
  • 1988-10-27 EP EP88910155A patent/EP0353262A1/en not_active Withdrawn
  • 1988-10-27 HU HU886797A patent/HUT51894A/hu unknown
  • 1988-10-27 WO PCT/SE1988/000574 patent/WO1989004178A1/en not_active Application Discontinuation
• 1989
  • 1989-07-03 DK DK329289A patent/DK329289A/da not_active Application Discontinuation

Non-Patent Citations (1)

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