WO1989004178A1 - New therapeutical use of h2-receptor-blocking compounds - Google Patents
New therapeutical use of h2-receptor-blocking compounds Download PDFInfo
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- WO1989004178A1 WO1989004178A1 PCT/SE1988/000574 SE8800574W WO8904178A1 WO 1989004178 A1 WO1989004178 A1 WO 1989004178A1 SE 8800574 W SE8800574 W SE 8800574W WO 8904178 A1 WO8904178 A1 WO 8904178A1
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- Prior art keywords
- treatment
- receptor
- compound
- bone
- medicament
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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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Abstract
A method for the treatment of osteoporosis, Paget's disease of bone, hyperparathyroidism, malignant neoplasms causing hypercalcinemia, parodontal diseases and prosthetic and implant-related bone loss, comprising administration to a patient suffering therefrom, an amount of H2-receptor-blocking compound or a pharmaceutically acceptable salt thereof. H2-receptor-blocking compounds for use in the manufacture of a medicament for such diseases are also disclosed as well as pharmaceutical preparations containing an H2-receptor-blocking compound for use in the treatment of said diseases. The preferred H2-receptor-blocking compounds are cimetidine and ranitidine.
Description
New therapeutical use of HL-receptor-blocking compounds
Field of the Invention
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.
Background of the Invention
The balance in normal subjects between on the one hand bone formation, which is associated with the number and activity of osteoblasts, that is cells associated with the production of bone in the organism, and on the other hand bone loss, which is associated with the number and activity of osteoclasts, that is cells associated with the absorption and removal of bone, is disturbed in several bone affecting diseases. At the present time there is no good treatment for any of these diseases, among which can be mentioned osteoporosis, Paget's disease of bone, hyperparathyroidism and related disorders, and several malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia.
Worldwide the most urgent need is for the treatment of osteoporosis and tumor associated hypercalcemia. In some areas, e.g. in England and in some other parts of Europe there is also high incidence of Paget's disease of bone.
In 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 poε_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).
The clinical manifestations of osteoporosis comprise fractures, especially hip fractures, but also vertebral fractures and fractures of the proximal radius, and complication of such fractures.
In Finland it has been estimated that about 10% of all surgical hospital beds are used for the treatment of osteoporosis related fractures (Lϋthje, P.: Reisiluunkaulan ja trokantterin murtumapotilaiden hoito ja ennuste seka hiodon kustannukset. Thesis. Helsinki 1983).
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.
Several 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-1α)-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).
In malignant hypercalcemia calcitonin and diphosphonate treatment has been used.
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.
Other disease states for the treatment of which antagonists to osteoclastic activity might be useful, are parodontal diseases and prostetic and implant bone losses.
It is an object of the present invention to provide compounds which by affecting the balance between osteoblast and osteoclast activity can be useful for prophylactic and therapeutic treatment of diseases as indicated above which are associated with bone loss. It is believed that the use of these compounds will also ultimately result in an increase of the bone mass.
Outline of the Invention
According to the present invention it has been found that the class of compounds known as H2-receptor-blocking agents, as well as pharmaceutically acceptable salts thereof, 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.
Examples of H2-receptor-blocking agents are:
Cimetidine
2-cyano-1-methyl-3-[2-[[5-methylimidazole-4-yl)-methyl]- thio]ethyl]guanidine
Ranitidine
N-[2-[[5-[(dimethylamino)methyl]furfuryl]thio]-ethyl]-N1- methyl-2-nitro-1,1-ethene-diamine
Famotidine
3- [ [ [ [ 2- (diajminomethylene) amino] -4-thiazolyl3methyl ]thio]-N- sulfamoylpropionamidine
BL-6341 A
3-[(2-guadinyl-4-thiazolyl)methγlthioethylamino]-4-amino-
1.2.5-thiadiazole monoxide
Ebrotidine p-bromo-N-[[[2-[[[2-[(diaminomethylene)amino]-4- thiazolyl]methyl]thio]ethyl]amino]methylene]benzenesulfonamide
Zaltidine [4-(2-methylimidazol-5-yl)-2-thiazolyl]guanidine
Nizatidine
N-[2-[[[2-[(dimethylamino)methyl]-4- thiazolyl]methyl]thio]ethyl]-N1-methγl-2-nitro-1,1- ethenediamine
Ramixotidine
N-[2-[[[5-[(dimethylamino)methyl3-2-furanyl]methyl]- thio]ethyl]-3-pyridinecarboxamide 1-oxide
BMY-25271
3-amino-4-[2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino]-1 2 5 -thiadiazole 1-oxide
1-[m-[3-[[1-methyl-3-[(methylsulfonyl)methyl]-1H-1,2,4- triazol-5-yl]amino3propoxy]benzyl]piperidine
Roxatidine
N-[3-[α -piperidino-m-tolyloxy3propy13carbamoylmethyl acetate
BMY - 25368
1-[3-(piperidinomεthyl)phenoxypropγlamino]-2-amino-3,4- dioxocyclobut-1-ene
Donetidine
5-(1,2-dihydro-2-oxoρyrid-4-ylmethyl)-2-[2-[s-(dimethylaininomethyl)furan-2-ylmethylthio]-ethylamino]pyrimidin-4(1H)-one
Tiotidine
1-[[2-(diaminomethyleneamino)-thiazole-4-yl]methylthioethyl]-2,3-dimethylguanidine
5-(3,4-methylendioxybenzyl)-2-[2-[5-methylimidazole-4- ylmethylthio]ethylamino]-pyrimidine-4(1H)-one
Mitentidine
N-[4(-imidazol-4-yl)-phenyl3-N1-isopropylformamidine
The preferred H2-blocking agents are cimetidine and ranitidine.
Accordingly, the invention relates to
- a method for the prophylactic and therapeutic treatment of each of the ailments above by administering to a host in need thereof of a therapeutically effective amount of a H2-receptor-blocking agent
- a pharmaceutical preparation for use in the prophylactic and therapeutic treatment of each of the ailments above comprising a H2-receptor-blocking agent as active ingredient
- a H2-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 H2-receptor -blocking agent.
Pharmacological tests
Sprague-Dawley male rats (Alab, Stockholm, Sweden) weighing 175-200 g before the tests were used. They obtained a standard diet consisting of rat feed pellets (Alab, Stockholm, Sweden) and tap water. Nine rats were given ranitidine (Hassle, Sweden) 1700 μmol/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.
45Ca incorporation into the skeleton
2 × 106 cpm 45CaCl2 (Radiochemical Center, Amersham, England) were administered orally by ventricular sond. The rats were killed by tapping blood via abdominal aorta 4 hours after the peroral administration of 45Ca. Radius, sternum, tibia and femur were removed by dissection. Radius and sternum were cleaned, weighed and placed in an oven at 800°C during 24 hours. The ashes were weighed and dissolved in 1M HCl. 10 ml Picofluor-40 (Packard) was added, whereafter the tubes were closed and shaken vigourosly before counting in a Beckman β-counter.
Radioimmunoanalysis of gastrin
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).
Operations were performed under ether anaesthesia. Fundectomia, comprising resection of the acid producing part of the ventricle, was performed as has been described in detail by Alumets et al (Alumets, J. , El Munshid, H.A., Hakansson, R., Hedenbro, J., Liedberg, G., Oscarson, J., Rehfeld, J.F., Sundler, F. and Vallgren, S., Gastrin cell proliferation after chronic stimulation. Effects of vagal denervation or gastric surgery in the rat. J. Physiol. 298, 557-569 (1980)). 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.
Description of the drawings
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 and 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. The stars designate the significance (i.e. the difference between control and test substance according to Student's t-test p < 0,05 = x; p < 0,01 = xx and p < 0,005 = xxx).
Test results
Ranitidine-treated rats and fundectomized rats developed pronounced and constant hypergastrinemia, which is seen in Fig. 1. The hypergastrinemia which had been developed by treatment with ranitidine stimulated 45Ca-incorporation into the skeleton, which is seen in Fig. 2. Hypergastrinemia caused by fundectomia did not stimulate 45Ca-incorporation into the skeleton.
The tests given above show clearly that treatment with ranitidine led to increased incorporation of calcium into the skeleton. This may be due to hypergastrinemia which in turn via some factor in the acid-producing part of the stomach seems to control the incorporation of calcium into the skeleton.
For clinical use the compounds in known manner are formulated into pharmaceutical formulations for oral, rectal, parεnteral or other mode of administration. Ihε 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. Usually 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.
Claims
1. A method for the treatment of osteoporosis by administering to a host in need of such treatment of a therapeutically effective amount of a H2-receptor- blocking compound, optionally together with a pharmaceutically acceptable carrier.
2. A method according to claim 1 where the H2-receptor- blocking compound is cimetidine or ranitidine.
3. A method for the treatment of Paget's disease of bone by administering to a host in need of such treatment of a therapeutically effective amount of a compound as defined in claims 1 or 2, optionally together with a pharmaceutically acceptable carrier.
4. A method for the treatment of primary and secondary hyperparathyroidism by administering to a host in need of such treatment of a therapeutically effective amount of a compound as defined in claims 1 or 2, optionally together with a pharmaceutically acceptable carrier.
5. A method for the treatment of such malignant neoplasms where tumor cells are producing osteoclast-activating factors, by administering to a host in need of such treatment of a therapeutically effective amount of a compound as defined in claims 1 or 2, optionally together with a pharmaceutically acceptable carrier.
6. A metod for the treatment of parodontal diseases, by administering to a host in need of such treatment of a therapeutically effective amount of a compound as defined in claims 1 or 2, optionally together with a pharmaceutically acceptable carrier.
7. A method for the treatment of prostetic and implantrelated bone loss, by administering to a host in need of such treatment of a therapeutically effective amount of a compound as defined in claims 1 or 2, optionally together with a pharmaceutically acceptable carrier.
8 . A method for the treatment of diseases connected with increased bone resorption by administering to a host in need of such treatment of a therapeutically effective amount of a compound as defined in claims 1 or 2, optionally together with a pharmaceutically acceptable carrier.
9. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of osteoporosis.
10. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of Paget' s disease of bone.
11. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of primary and secondary hyperparathyroidism.
12. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of such malignant neoplasms where tumor cells are producing osteoclast activating factors.
13. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of parodontal diseases.
14. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of prostetic and implant-related bone loss.
15. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of diseases connected with increased bone resorption.
16. A pharmaceutical preparation for use in the treatment of osteoporosis; Paget's disease of bone; primary and secondary hyperparathyroidism; such malignant neoplasms where tumor cells are producing osteoclast-activating factors; such parodontal diseases which are associated with bone loss; or prostetic and implant-related bone loss; and comprising a compound of the formula I as defined in claim 1 as active ingredient.
17. A method for increasing the incorporation of calcium into the skeleton by administering a sufficient amount of a H2-receptor-blocking compound as defined in claims 1 or 2.
18. A H2-receptor-blocking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for the treatment of ailments requiring increased corporation of calcium into the skeleton.
19. A pharmaceutical preparation for use in the treatment of ailments requiring increased incorporation of calcium into the skeleton comprising a H2-receptor-blocking compound as active ingredient.
20. A method for improving the healing rate of bone fractures by administering to a host in need thereof of an affective amount of a H2-receptor-blocking compound, as defined in claims 1 or 2.
21. A H2-receptor-bloσking compound as defined in claims 1 or 2 for use in the manufacture of a medicament for improving the healing rate of bone fractures.
22. A pharmaceutical preparation for use in improving the healing rate of bone fractures, comprising a
H2-receptor-blocking compound as defined in claims 1 or 2 as active ingredient.
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| DK329289A DK329289A (en) | 1987-11-13 | 1989-07-03 | NEW THERAPEUTIC USE OF H2 RECEPTOR BREAKING COMPOUNDS |
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| SE8704436-8 | 1987-11-13 | ||
| SE8704436A SE8704436D0 (en) | 1987-11-13 | 1987-11-13 | USE OF ANTI-SECRETARY SUBSTANCES FOR NEW INDICATIONS |
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| EP (1) | EP0353262A1 (en) |
| JP (1) | JPH02502188A (en) |
| AU (1) | AU2720388A (en) |
| DK (1) | DK329289A (en) |
| HU (1) | HUT51894A (en) |
| SE (1) | SE8704436D0 (en) |
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Cited By (9)
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| WO1993020815A1 (en) * | 1992-04-15 | 1993-10-28 | The Procter & Gamble Company | Use of h-2 antagonists for treatment of gingivitis |
| SG139556A1 (en) * | 1997-07-22 | 2008-02-29 | Merck & Co Inc | Method for inhibiting bone resorption |
| US9463199B2 (en) | 2004-03-25 | 2016-10-11 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| US9616134B2 (en) | 2006-11-07 | 2017-04-11 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising pimobendan |
| US10071162B2 (en) | 2013-07-19 | 2018-09-11 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
| US10117869B2 (en) | 2004-03-25 | 2018-11-06 | Boehringer Ingelheim Vetmedica Gmbh | PDE III inhibitors for treatment of asymptomatic heart failure |
| US10172804B2 (en) | 2013-12-04 | 2019-01-08 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical compositions of pimobendan |
| US10398705B2 (en) | 2012-03-15 | 2019-09-03 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
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| GB8629781D0 (en) * | 1986-12-12 | 1987-01-21 | Glaxo Group Ltd | Pharmaceutical compositions |
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| US9889148B2 (en) | 2004-03-25 | 2018-02-13 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size in mammals suffering from heart failure |
| US11413285B2 (en) | 2004-03-25 | 2022-08-16 | Boehringer Ingelheim Vetmedica Gmbh | PDE III inhibitors for treatment of asymptomatic heart failure |
| US10117869B2 (en) | 2004-03-25 | 2018-11-06 | Boehringer Ingelheim Vetmedica Gmbh | PDE III inhibitors for treatment of asymptomatic heart failure |
| US9616134B2 (en) | 2006-11-07 | 2017-04-11 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising pimobendan |
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| US10398705B2 (en) | 2012-03-15 | 2019-09-03 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
| US11185590B2 (en) | 2013-07-19 | 2021-11-30 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
| US10071162B2 (en) | 2013-07-19 | 2018-09-11 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
| US12357696B2 (en) | 2013-07-19 | 2025-07-15 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
| US10172804B2 (en) | 2013-12-04 | 2019-01-08 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical compositions of pimobendan |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
| US12011441B2 (en) | 2016-04-06 | 2024-06-18 | Boehringer Ingelheim Vetmedica Gmbh | Pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0353262A1 (en) | 1990-02-07 |
| HUT51894A (en) | 1990-06-28 |
| SE8704436D0 (en) | 1987-11-13 |
| AU2720388A (en) | 1989-06-01 |
| DK329289D0 (en) | 1989-07-03 |
| JPH02502188A (en) | 1990-07-19 |
| HU886797D0 (en) | 1990-05-28 |
| DK329289A (en) | 1989-07-03 |
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