NL8004904A - MEDICINE AGAINST BONE MINERAL RESORPTION. - Google Patents
MEDICINE AGAINST BONE MINERAL RESORPTION. Download PDFInfo
- Publication number
- NL8004904A NL8004904A NL8004904A NL8004904A NL8004904A NL 8004904 A NL8004904 A NL 8004904A NL 8004904 A NL8004904 A NL 8004904A NL 8004904 A NL8004904 A NL 8004904A NL 8004904 A NL8004904 A NL 8004904A
- Authority
- NL
- Netherlands
- Prior art keywords
- bone
- allergic
- treatment
- disodium chromoglycate
- carbon atoms
- Prior art date
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- 210000000988 bone and bone Anatomy 0.000 title claims description 45
- 229910052500 inorganic mineral Inorganic materials 0.000 title claims description 25
- 239000011707 mineral Substances 0.000 title claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 17
- 230000003266 anti-allergic effect Effects 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 claims description 14
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 13
- SOWBFZRMHSNYGE-UHFFFAOYSA-N oxamic acid Chemical compound NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 238000010521 absorption reaction Methods 0.000 claims description 11
- 229930003316 Vitamin D Chemical class 0.000 claims description 9
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 239000011710 vitamin D Chemical class 0.000 claims description 9
- 235000019166 vitamin D Nutrition 0.000 claims description 9
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 9
- 229940046008 vitamin d Drugs 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- RVGLGHVJXCETIO-UHFFFAOYSA-N lodoxamide Chemical group OC(=O)C(=O)NC1=CC(C#N)=CC(NC(=O)C(O)=O)=C1Cl RVGLGHVJXCETIO-UHFFFAOYSA-N 0.000 claims description 8
- 230000001575 pathological effect Effects 0.000 claims description 8
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- 150000003431 steroids Chemical class 0.000 claims description 7
- 102000055006 Calcitonin Human genes 0.000 claims description 6
- 108060001064 Calcitonin Proteins 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000003263 anabolic agent Substances 0.000 claims description 6
- 229940070021 anabolic steroids Drugs 0.000 claims description 6
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims description 6
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 5
- 159000000007 calcium salts Chemical class 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
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- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
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- VFFTVZUIDYJUQS-UHFFFAOYSA-N 5-hydroxy-4-oxo-10-propyl-6,7,8,9-tetrahydrobenzo[g]chromene-2-carboxylic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1CCCCC1=C2O VFFTVZUIDYJUQS-UHFFFAOYSA-N 0.000 claims description 3
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- 150000002431 hydrogen Chemical class 0.000 claims 2
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- 230000001599 osteoclastic effect Effects 0.000 description 8
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- 208000006386 Bone Resorption Diseases 0.000 description 6
- 230000024279 bone resorption Effects 0.000 description 6
- 208000028169 periodontal disease Diseases 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 150000001562 benzopyrans Chemical class 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 description 3
- 206010065687 Bone loss Diseases 0.000 description 3
- 208000010191 Osteitis Deformans Diseases 0.000 description 3
- 208000027868 Paget disease Diseases 0.000 description 3
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- 229940088597 hormone Drugs 0.000 description 3
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
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- 238000005115 demineralization Methods 0.000 description 2
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- KBEVFOCEDVDQII-UHFFFAOYSA-N 2-[2-(oxaloamino)anilino]-2-oxoacetic acid Chemical class OC(=O)C(=O)NC1=CC=CC=C1NC(=O)C(O)=O KBEVFOCEDVDQII-UHFFFAOYSA-N 0.000 description 1
- PQJZHMCWDKOPQG-UHFFFAOYSA-N 2-anilino-2-oxoacetic acid Chemical class OC(=O)C(=O)NC1=CC=CC=C1 PQJZHMCWDKOPQG-UHFFFAOYSA-N 0.000 description 1
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- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
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- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
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Classifications
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pulmonology (AREA)
- Organic Chemistry (AREA)
- Birds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Pyrane Compounds (AREA)
Description
ί ^ \ί ^ \
Geneesmiddel tegen resorptie van botmineraal.Medicine against resorption of bone mineral.
De uitvinding heeft betrekking op een geneesmiddel tegen pathologische resorptie van botmineraal, in het bijzonder die waarbij de bot- of tandstructuur verdwijnt,The invention relates to a medicament against pathological absorption of bone mineral, in particular that in which the bone or tooth structure disappears,
Resorptie van botmineraal waarbij de tandstruc-5 tuur verdwijnt omvat bijvoorbeeld oppervlakte en/of inflammatoire resorptie van de tandwortelstructuur en dentale ankylose met vervanging resorptie.Bone mineral resorption with the tooth structure disappearing includes, for example, surface and / or inflammatory resorption of the tooth root structure and dental ankylosis with replacement resorption.
De uitvinding heeft meer in het algemeen betrekking op een geneesmiddel tegen osteoporose. Osteoporose is een aan-10 doening waarbij een vermindering optreedt in de dichtheid van het botweefsel (collageen) en botmineraal (Ca10(PO4)g(0H)2 of hydroxy-apatiet)’» Deze abnormale rarefactio is een gevolg van een stoornis in de bot- of beenvorming door osteoblasten, dat zijn bot- of been-vormende bindweefselcellen die samenwerking met osteoclasten, en 15 dat zijn cellen die beenweefsel afbreken en resorberen. Rarefactio kan ook een gevolg zijn van overmatige osteoclastische activiteit, of van een stoornis in het osteoblastisch-osteoclastisch evenwicht. Rarefactio van bot is een aandoening waarbij de massa maar niet het volume van het bot afneemt. Osteoporose komt voornamelijk voor bij 20 volwassenen en kan zich op talloze manieren manifesteren, onder meer in rugpijn en vervorming van het ruggemerg. De botten worden bros waardoor de kans op breuk toeneemt. Verschillende soorten van osteoporose zijn beschreven in Dorland's Illustrated Medical Dictionary, 24e druk, W.B. Saunders Company, Londen (1965). Tot de verschillende 25 soorten osteoporose behoren seniele osteoporose ten gevolge van ouder worden, osteoporose die optreedt na de menopauze en samenhangt met een vermindering van de ovariale produktie van estrogeen die op de menopauze volgt, osteoporose optredend bij langdurige immofiili-satie, en steroidale osteoporose als gevolg van behandeling met 8004904 2 anti-inflammatoire steroiden. Andere ziektes die het gevolg zijn van langdurige pathologische resorptie van botmineraal zijn Paget's disease, rheumatolde arthritis en peridontale aandoening. Paget's disease wordt gekarakteriseerd door botdecalcificatie en botverwe-5 king gevolgd door abnormale kalkafzetting. Zowel bij Paget's disease als rheumatolde arthritis treedt botvervorming op. Bij rheumatolde arthritis leidt de ontsteking van synoviale weefsels tot deminerali-satie vein aangrenzende botoppervlakken en abnormale mineralisatie van niet-aangrenzende botoppervlakken. Op de lange duur treedt immo-10 bilisatie van de gewrichten op ten gevolge van voortschrijdende misvorming van de botstructuur. Peridontale aandoening wordt eveneens gekarakteriseerd door pathologische resorptie van botmineraal. Het gevolg daarvan is dat het alveolaire bot dat de tand draagt en vasthoudt, wordt geresorbeerd met tot gevolg dat de aangetaste tand uit-15 valt.More generally, the invention relates to an anti-osteoporosis drug. Osteoporosis is a condition in which a decrease in the density of bone tissue (collagen) and bone mineral (Ca10 (PO4) g (0H) 2 or hydroxyapatite) occurs. »» This abnormal rarefactio is due to a disturbance in the bone or bone formation by osteoblasts, which are bone or bone-forming connective tissue cells that cooperate with osteoclasts, and which are cells that break down and resorb bone tissue. Rarefactio can also be a result of excessive osteoclastic activity, or of a disturbance in the osteoblastic-osteoclastic balance. Bone rarefactio is a condition in which the mass but not the volume of the bone decreases. Osteoporosis mainly occurs in 20 adults and can manifest in countless ways, including back pain and spinal deformity. The bones become brittle, which increases the risk of fracture. Different types of osteoporosis are described in Dorland's Illustrated Medical Dictionary, 24th ed., W.B. Saunders Company, London (1965). The different types of osteoporosis include senile osteoporosis due to aging, osteoporosis that occurs after menopause and is associated with a reduction in ovarian production of estrogen following menopause, osteoporosis occurring with prolonged immophilisation, and steroidal osteoporosis as as a result of treatment with 8004904 2 anti-inflammatory steroids. Other diseases that result from long-term pathological resorption of bone mineral are Paget's disease, rheumatoid arthritis and periodontal disease. Paget's disease is characterized by bone decalcification and bone softening followed by abnormal calcification. Bone deformity occurs in both Paget's disease and rheumatoid arthritis. In rheumatoid arthritis, the inflammation of synovial tissues leads to demineralization of adjacent bone surfaces and abnormal mineralization of non-adjacent bone surfaces. In the long run, immobilization of the joints occurs due to progressive deformity of the bone structure. Periodontal disease is also characterized by pathological absorption of bone mineral. As a result, the alveolar bone that carries and holds the tooth is absorbed with the result that the affected tooth falls out.
Als oorzaak van botontkalking kan worden genoemd hyperparathyreoidie (overmatige functie van de bijschildklieren) waardoor de osteoclastische activiteit wordt gestimuleerd, en verder, in vele neoplastische aandoeningen, de neoplasmata (nièw-vormingen) 20 die bij contact met bot of been pathologische resorptie van mineraal induceren. Voorbeelden van dergelijke neoplasmata zijn borstklier-carcinoomcellen en plasmacytomas zoals multipele myloma. Van multipele myloma is bekend dat deze aandoening de vorming van overmatige hoeveelheden osteoclastische activeringsfactor (OAP) induceert met 25 tot gevolg overmatige osteoclastische activiteit en daarmee van bot-resorptie.Hyperparathyroidism (excessive function of the parathyroid glands) which stimulates osteoclastic activity can be mentioned as a cause of bone loss, and furthermore, in many neoplastic diseases, the neoplasms (new formations) which induce pathological absorption of mineral on contact with bone or bone. . Examples of such neoplasms are mammary gland carcinoma cells and plasma cytomas such as multiple myloma. Multiple myloma is known to induce the formation of excessive amounts of osteoclastic activation factor (OAP) resulting in excessive osteoclastic activity and hence bone resorption.
Voor andere oorzaken van botmineraalresorptie dam verhoogde osteoclastische activiteit, verstoring vam het osteo-blastisch-osteroclastisch evenwicht en/of infiltratie van neoplasti-30 sche cellen in beenweefsels, wordt verwezen naau: Mindy, G.R. et al., "Direct Resorption of Bone by Human Monocytes", Science 196:1109-1111, 1977: Heersche, J.N.M., "The Mechanism of Osteoclastic Bone Resorption: A New Hypothesis", Proceedings, Mechanism of Localized Bone Loss, Eds., Horton, Tarpley en Davis, Special Supplement to 35 Calcified Tissue Abstracts, biz. 437-438, 1978: en Teitelbaum, S.L.For other causes of bone mineral resorption, increased osteoclastic activity, disturbance of the osteoblastic-osteroclastic balance and / or infiltration of neoplastic cells into bone tissues, see: Mindy, G.R. et al., "Direct Resorption of Bone by Human Monocytes", Science 196: 1109-1111, 1977: Heersche, JNM, "The Mechanism of Osteoclastic Bone Resorption: A New Hypothesis", Proceedings, Mechanism of Localized Bone Loss, Eds. , Horton, Tarpley, and Davis, Special Supplement to 35 Calcified Tissue Abstracts, biz. 437-438, 1978: and Teitelbaum, S.L.
8004904 » N» 3 et al., "Contact-Mediated Bone Resorption by Human Monocytes in Vitro", Proceedings, Mechanism of Localized Bone Loss, Eds., Horton, Tarpley en Davis, Special Supplement tot Calcified Tissue Abstracts, biz.8004904 »N» 3 et al., "Contact-Mediated Bone Resorption by Human Monocytes in Vitro", Proceedings, Mechanism of Localized Bone Loss, Eds., Horton, Tarpley and Davis, Special Supplement to Calcified Tissue Abstracts, biz.
443, 1978.443, 1978.
5 Voor het behandelen en voorkomen van osteoporose zijn talrijke anti-osteoporotische middelen bekend, bijvoorbeeld anabole steroiden, verschillende fosfor-bevattende middelen, vitamine D en verwante verbindingen, oestrogene steroiden en calcitonine.Numerous anti-osteoporotic agents are known for treating and preventing osteoporosis, for example anabolic steroids, various phosphorus-containing agents, vitamin D and related compounds, estrogenic steroids and calcitonin.
Daarnaast hebben bepaalde aromatische carbonzuren bekendheid verkre-10 gen als anti-osteoporotische middelen. Voor nadere bijzonderheden over anti-osteoporotische middelen wordt verwezen naar de Amerikaanse octrooischriften 4.125.621 en 4.101.668.In addition, certain aromatic carboxylic acids have become known as anti-osteoporotic agents. For details on anti-osteoporotic agents, see U.S. Patents 4,125,621 and 4,101,668.
Om de anti-osteoporotische eigenschappen van een verbinding vast te stellen zijn een groot aantal methoden ontwikkeld.Numerous methods have been developed to determine the anti-osteoporotic properties of a compound.
15 Bij één daarvan wordt de invloed bepaald van de onderzochte verbinding op de vorming van cyclisch AMP onder gebruikmaking van geïsoleerde beenweefselcellen als testmedium. Deze methode is beschreven door Rodan et al., J.B.C. 429:306 (1974) en Rodan et al., Science 189:467 (1975),,en meer gedetailleerd in het Amerikaans octrooischrift 20 4.125.621 voorbeeld l.In one of these, the influence of the tested compound on the formation of cyclic AMP is determined using isolated bone tissue cells as the test medium. This method has been described by Rodan et al., J.B.C. 429: 306 (1974) and Rodan et al., Science 189: 467 (1975), and in more detail in U.S. Patent No. 4,125,621, Example 1.
Een doeltreffende methode om de remming van bot-mineraal resorptie door een verbinding vast te stellen, is beschreven door Horton, J.E. et al., "Inhibition of In Vitro Bone Resorption by a Cartilage-Derived Anticollagenase Factor", Science 199:1342-25 1345 (24 maart 1978). Deze methode berust op het vaststellen van het vermogen van de onderzochte verbinding om osteoclastische active- ringsfactor, prostaglandine en parathyreoide hormoon-gestimuleerde 45An effective method to assess the inhibition of bone mineral resorption by a compound has been described by Horton, J.E. et al., "Inhibition of In Vitro Bone Resorption by a Cartilage-Derived Anticollagenase Factor", Science 199: 1342-25 1345 (March 24, 1978). This method relies on assessing the investigated compound's ability to produce hormone-stimulated osteoclastic activation factor, prostaglandin and parathyroid hormone.
Ca afgifte door foetaal rattebot in vitro te blokkeren. Voor het verband tussen de osteoclastische activiteit op botmineraal resorp-30 tie en de verhoging van botmineraal resorptie geïnduceerd door parathyreoide hormoon-stimulering in vivo en in vitro, wordt verwezen naar Rasmussen et al., "The Physiologic and Cellular Basis of Metabolic Bone Disease", Williams & Williams, Baltimore, 1974, biz.Ca release by blocking fetal rat bone in vitro. For the relationship between osteoclastic activity on bone mineral resorption and the enhancement of bone mineral resorption induced by parathyroid hormone stimulation in vivo and in vitro, see Rasmussen et al., "The Physiologic and Cellular Basis of Metabolic Bone Disease" , Williams & Williams, Baltimore, 1974, biz.
144-154.144-154.
35 De techniek van Horton voornoemd voor het bepalen 80 0 4 90 4 4 van de remming van botmineraal resorptie onder gebruikmaking van been-weefselcultuurcellen, is beschreven door Raisz L.G. et al., Endocrinology 85:446 (1969). Daarbij worden met elkaar verbonden schachten van de radius (spaakbeen) en ulna (ellepijp) afkomstig van 19 5 dagen oude rattefoetera radio-actief gemerkt door de moeder te injec-45 teren met Ca. Een dag later worden de schachten gekweekt in het beschreven medium dat (eventueel) de onderzochte verbinding en/of een botresorptie stimulerend middel zoals het parathyreolde hormoon bevat. Door elke 48 uren parathyreolde hormoon toe te voegen in een 10 hoeveelheid van bijvoorbeeld 2,5 Iü, wordt de mineraal resorptie uit het bot gestimuleerd. Het kweken wordt gedurende 120-144 uren uitgevoerd waarbij het medium om de 48 uren wordt vervangen. Als maatstaf 45 voor de botmineraal resorptie wordt genomen het percentage Ca afgegeven door het bot aan het medium. Dit percentage wordt bepaald 15 door vloeistofscintillatie.The Horton technique aforementioned for determining the inhibition of bone mineral resorption using bone tissue culture cells has been described by Raisz L.G. et al., Endocrinology 85: 446 (1969). In addition, interconnected shafts of the radius (radius bone) and ulna (ulna) from 19 day old rat foetera are radiolabelled by injecting the mother with Ca. A day later, the shafts are grown in the described medium containing (optionally) the tested compound and / or a bone resorption stimulant such as the parathyroid hormone. By adding parathyreolde hormone in an amount of, for example, 2.5 µl every 48 hours, the mineral absorption from the bone is stimulated. Culturing is carried out for 120-144 hours with the medium being replaced every 48 hours. The measure of bone mineral resorption is the percentage of Ca delivered by the bone to the medium. This percentage is determined by liquid scintillation.
Het werkzame bestanddeel in de geneesmiddelen volgens de uitvinding wordt gevormd door bekende verbindingen met anti-allergische werking# in het bijzonder dinatriumchromoglycaat en daarmee verwante anti-allergische bischromonen en benzopyranen.The active ingredient in the medicaments according to the invention are known compounds with antiallergic activity, in particular disodium chromoglycate and related antiallergic bischromones and benzopyranes.
20 Met dinatriumchromoglycaat verwante anti-allergische chromonen zijn beschreven in de Amerikaanse octrooischriften 3.419.578, 3.519.652, 3.673.218 en 4,046.910. Met dinatriumchromoglycaat verwante anti-allergische benzopyranen zijn beschreven in de Amerikaanse octrooischriften 4.159.273, 3.786.071, 3.952.104 en 4.055.654. Een waarde-25 volle verbinding is proxicromil (FPL 57,787), dat is 6,7,8,9-tetra-hydro-5'-hydroxy-4-oxo-10-propyl-4H-nafto/~2,3-6_/pyran-2-carbonzuur, beschreven in voorbeeld 8 van voornoemd Amerikaans octrooischrift 4.159.273.Disodium chromoglycate-related antiallergic chromones are described in U.S. Pat. Nos. 3,419,578, 3,519,652, 3,673,218, and 4,046,910. Disodium chromoglycate-related anti-allergic benzopyranes are described in U.S. Patents 4,159,273, 3,786,071, 3,952,104, and 4,055,654. A value-25 full compound is proxicromil (FPL 57.787), which is 6,7,8,9-tetra-hydro-5'-hydroxy-4-oxo-10-propyl-4H-naphtho ~ ~ 2,3-6. / pyran-2-carboxylic acid, described in Example 8 of the aforementioned U.S. Patent 4,159,273.
Daarnaast komen als werkzaam bestanddeel in de 30 geneesmiddelen volgens de uitvinding in aanmerking anti-allergische oxamidezuren of derivaten daarvan. Dergelijke verbindingen zijn beschreven in de Amerikaanse octrooischriften 3.993.679, 4.159.278, 4.095.028, 4.089.973, 4.011.337, 4.091.011, 3.972.911, 4.067.995, 3.980.660, 4.044.148, 3.982.006, 4.061.791, 4.017.538, 4.119.783, 35 4.113.880, 4.128.660, 4.150.140, 3.966.965, 3.963.660, 4.038.398, 80 04 90 4 ψ -Ρ 5 3.987.192, 3.852.324, 3.368.541 en 3.836.164. Een waardevol anti-allergische verbinding van dit type is lodoxamide, dat is het dubbel-zout van N,N'-(2-chloor-5-cyano-m-fenyleen)dioxamidezuur en tris-(hydroxymethyl) aminomethaan.In addition, as active ingredient in the medicaments according to the invention, anti-allergic oxamic acids or derivatives thereof are suitable. Such compounds are described in U.S. Pat. Nos. 3,993,679, 4,159,278, 4,095,028, 4,089,973, 4,011,337, 4,091,011, 3,972,911, 4,067,995, 3,980,660, 4,044,148, 3,982. 006, 4.061.791, 4.017.538, 4.119.783, 35 4.113.880, 4.128.660, 4.150.140, 3.966.965, 3.963.660, 4.038.398, 80 04 90 4 ψ -Ρ 5 3,987,192 , 3,852,324, 3,368,541 and 3,836,164. A valuable antiallergic compound of this type is lodoxamide, which is the double salt of N, N '- (2-chloro-5-cyano-m-phenylene) dioxamic acid and tris- (hydroxymethyl) aminomethane.
5 Andere anti-osteoporotische middelen zijn be schreven in de Amerikaanse octrooischriften 4.125.612 en 4.101.663.Other anti-osteoporotic agents are described in U.S. Patents 4,125,612 and 4,101,663.
Voor wat dinatriumchromoglycaat betreft, kan nog worden vermeld, dat deze verbinding degranulatie van mastoid cellen in apegingiva (tandvlees) remt, maar geen waarneembare in-10 vloed heeft op gingivitis (tandvleesontsteking) bij apen. ZieAs far as disodium chromoglycate is concerned, it should be noted that this compound inhibits degranulation of mastoid cells in apegingiva (gum), but has no discernible effect on gingivitis (gingivitis) in monkeys. See
Nuki, K., el., "The Inhibition of Mast Cell Degranulation in Monkey Gingiva by Disodium Cromoglycate”, J. Periodontal. Res. 10:282-287 (1975), Goldhaber, P., "Heparin Enchancement of Factors Stimulating Bone Resorption in Tissue Culture", Science 147: 407-408 (1965) en 15 Shapiro, S. et al., "Mass Cell Population in Gingiva Affected by Chronic Destructive Periodontal Disease", Periodontics 40:276-278 (1969).Nuki, K., el., "The Inhibition of Mast Cell Degranulation in Monkey Gingiva by Disodium Cromoglycate", J. Periodontal. Res. 10: 282-287 (1975), Goldhaber, P., "Heparin Enchancement of Factors Stimulating Bone Resorption in Tissue Culture ", Science 147: 407-408 (1965) and Shapiro, S. et al.," Mass Cell Population in Gingiva Affected by Chronic Destructive Periodontal Disease ", Periodontics 40: 276-278 (1969).
De geneesmiddelen volgens de uitvinding bevatten dus als werkzaam bestanddeel tenminste dinatriumchromoglycaat in 20 het vervolg afgekort met DNCG of wat in het hierna volgende een anti-allergisch DNCG bio-analogon wordt genoemd, en eventueel één of meer andere bekende anti-osteoporotische middelen zoals anabole steroïden, oestrogene steroiden, vitamine D en vitamine D metabo-lieten, fosfor-bevattende verbindingen, anorganische fluoride-bevat-25 tende verbindingen, calciumzouten en calcitonine. De anti-allergische DNCG bio-analoga omvatten andere anti-allergische bischromonen en benzopyranen dan dinatriumchromoglycaat en verder anti-allergische oxamidezuren of derivaten daarvan (oxamaten).The medicaments according to the invention thus contain as active ingredient at least disodium chromoglycate, abbreviated hereinafter with DNCG or what is hereinafter referred to as an anti-allergic DNCG bio-analog, and optionally one or more other known anti-osteoporotic agents such as anabolic steroids , estrogenic steroids, vitamin D and vitamin D metabolites, phosphorus-containing compounds, inorganic fluoride-containing compounds, calcium salts and calcitonin. The antiallergic DNCG bio-analogs include antiallergic bischromones and benzopyranes other than disodium chromoglycate and further antiallergic oxamic acids or derivatives thereof (oxamates).
De geneesmiddelen volgens de uitvinding komen in 30 aanmerking voor de volgende toepassingen: 1) behandelen of voorkomen van pathologische resorptie van botmineraal door systemisehe toediening van DNCG of een DNCG bio-analogon, eventueel samen met één of meer andere bekende anti-osteoporotische middelen bestaande uit anabole steroiden, 35 oestrogene steroiden, vitamine D of een vitamine D metaboliet, 8004904 6 fosfor-bevattende middelen, anorganische fluoride-bevattende middelen, calciumzouten en/of calcitonine, en 2) behandelen van ontstekingen met een anti-inflammatoir steroid en DNCG of een DNCG bio-analogon om patholo-5 gische resorptie van botmineraal te genezen of te voorkomen.The medicaments of the invention are eligible for the following uses: 1) treating or preventing pathological absorption of bone mineral by systemic administration of DNCG or a DNCG bio-analog, optionally together with one or more other known anti-osteoporotic agents consisting of anabolic steroids, 35 estrogenic steroids, vitamin D or a vitamin D metabolite, 8004904 6 phosphorus-containing agents, inorganic fluoride-containing agents, calcium salts and / or calcitonin, and 2) treating inflammation with an anti-inflammatory steroid and DNCG or a DNCG bio-analogue to cure or prevent pathological resorption of bone mineral.
De geneesmiddelen volgens de uitvinding kunnen worden toegepast in gebruikelijke farmaceutische vorm. Voor het behandelen van pathologische resorptie van dentaal botmineraal of periodontale aandoeningen kunnen de geneesmiddelen in de vorm verke-10 ren van een tandmiddel, tandpoeder, mondwater en dergelijke. Derhalve dient het begrip geneesmiddel in de meest ruime zin te worden verstaan.The medicaments of the invention can be used in conventional pharmaceutical form. For the treatment of pathological absorption of dental bone mineral or periodontal diseases, the drugs may be in the form of a dentifrice, toothpowder, mouthwash and the like. The term medicine should therefore be understood in the broadest sense.
De geneesmiddelen volgens de uitvinding komen niet alleen in aanmerking voor het behandelen van mensen maar ook 15 van dieren zoals runderen, paarden, konijnen en pluimvee. Voor het behandelen van dieren kunnen de geneesmiddelen in de vorm verke-ren van een diervoeder, diervoedersupplement of diervoederpremixThe medicaments according to the invention are not only suitable for the treatment of humans, but also of animals such as cattle, horses, rabbits and poultry. For the treatment of animals, the medicaments may be in the form of an animal feed, animal feed supplement or animal premix
Profylactisch worden de geneesmiddelen volgens de uitvinding toegepast bij langdurige behandeling met hoge doses 20 anti-inflammatoir steroid, bij ovario-hysterectomie, na de menopauze, bij ouderdom, bij chirurgische behandeling van aangetast, gedeformeerd of getransplanteerd been- of botweefsel, bij langdurige ruimtevaartreizen onder verminderde gravitatiekracht, bij renale dialyse, en bij elke kans op resorptie van botmineraal zoals bij 25 periodontale aandoeningen.Prophylactically, the medicaments according to the invention are used in long-term treatment with high doses of anti-inflammatory steroid, in ovario hysterectomy, after menopause, in old age, in surgical treatment of affected, deformed or transplanted bone or bone tissue, in long-term space travel under decreased gravitational force, with renal dialysis, and with any chance of bone mineral absorption as with periodontal diseases.
De profylactische dosis is in het algemeen iets lager dan de behandelingsdosis welke laatste dosis tijdens de therapie kan worden opgevoerd tot een maximale responsie is bereikt. Dit is het geval wanneer de demineralisatie begint af te nemen om geheel 30 of nagenoeg geheel te verdwijnen of tot een minimum te worden beperkt.The prophylactic dose is generally slightly lower than the treatment dose, which last dose can be increased during therapy until a maximum response is achieved. This is the case when the demineralization begins to decline to disappear completely or almost entirely or to be minimized.
DNCG wordt bij voorkeur toegediend door insuffla-tie in een dosis van 5-20 mg, of parenteraal in een equivalente dosis. Voor het remmen van botmineraal resorptie is deze verbinding 35 oraal niet werkzaam. Andere bischromonen dein DNCG worden eveneens 80 0 4 90 4 7 bij voorkeur toegediend door insufflatie. Voor nadere bijzonderheden hieromtrent wordt verwezen naar het Amerikaans octrooischrift 4.046.910, Oxamaten en benzopyranen kunnen oraal worden toegediend in een dosis van 0,1-100 mg. Voor het vaststellen van de juiste 5 dosis oxamaat of benzopyran wordt verwezen naar voornoemd Amerikaans octrooischrift 4.046.910.DNCG is preferably administered by insufflation at a dose of 5-20 mg, or parenterally at an equivalent dose. This compound is not effective orally to inhibit bone mineral absorption. Other bischromones in DNCG are also preferably administered by insufflation. For further details in this regard, reference is made to U.S. Pat. No. 4,046,910, Oxamates and Benzopyranes can be administered orally at a dose of 0.1-100 mg. For determining the correct dose of oxamate or benzopyran, reference is made to the aforementioned United States Patent Specification 4,046,910.
Zoals reeds vermeld worden de geneesmiddelen voor het behandelen van perlodontale aandoeningen bij voorkeur toegepast in een voor topische toediening geschikte vorm zoals tandpasta, 10 tandpoeder of mondwater. Dergelijke preparaten kunnen op gebruikelijke wijze worden bereid. Wanneer het DNCG bio-analogon oraal actief is, wordt het geneesmiddel bij voorkeur oraal toegediend.As already mentioned, the medicaments for treating periodontal disease are preferably used in a form suitable for topical administration such as toothpaste, tooth powder or mouthwash. Such preparations can be prepared in the usual manner. When the DNCG bio-analog is orally active, the drug is preferably administered orally.
Parenteraal kunnen de geneesmiddelen worden toegediend door intraveneuze injectie of infusie en door subcutane in-15 jectie. Ook deze preparaatvormen kunnen op gebruikelijke wijze worden bereid onder toepassing van steriele oplossingen voor injectie en infusie.The drugs can be administered parenterally by intravenous injection or infusion and by subcutaneous injection. These formulations can also be prepared in a conventional manner using sterile solutions for injection and infusion.
Voor zover de werkzame bestanddelen carboxylgroe-pen bevatten kunnen deze vrij zijn of in de vorm verkeren van esters 20 of zouten.Insofar as the active ingredients contain carboxyl groups, they may be free or in the form of esters or salts.
In combinatie met bekende anti-osteoporotische middelen zoals anabole steroiden, oestrogene steroïden, calcium-zouten, anorganische fluoriden en calcitonine (Amerikaans octrooischrift 4.125.621) kan het gehalte DNCG of DNCG bio-analogon in de 25 preparaten volgens de uitvinding aanmerkelijk worden teruggebracht tot niet lager dan 50 % om resorptie van botmineraal te beëindigen. Wanneer beide soorten werkzame bestanddelen gecombineerd worden toegepast, kunnen zij vóór de behandeling in afzonderlijk verpakte vorm verkeren.In combination with known anti-osteoporotic agents such as anabolic steroids, estrogenic steroids, calcium salts, inorganic fluorides and calcitonin (US Pat. No. 4,125,621), the DNCG or DNCG bio-analog content in the compositions of the invention can be significantly reduced to not lower than 50% to end bone mineral absorption. When used in combination, both types of active ingredients may be in individually packaged form prior to treatment.
30 Voorbeelden van bischromonen met anti-botmineraal resorptiewerking die de voorkeur hebben, zijn weergegeven met de formule 1 waarin Rj, R2, R3, R4, Rg en Rg waterstof, halogeen (chloor, broom of jood) lage alkyl (bij voorkeur alkyl met 1-4 koolstofatomen) hydroxy of lage alkoxy (bij voorkeur alkoxy met 1-4 koolstofatomen) 35 voorstellen, en X al dan niet vertakt polymethyleen met 3-7 koolstof- 80 04 90 4 8 atomen met inbegrip van -CH^-CH^CH-CH^-, -CH2~CH2-0-CH2-CH2-, -CE^-CO-CB^-, -CH2~(o-Ph)-CH2, waarin o-Ph 1,2-fenyleen is, -CH2-C(CH2OH)(CH2C1)-CH2-, -CH2-CH(OH)-CH2-, of -CH2-CH(0H)-CH2-O-CH^-CH(OH)-CH2- voorstelt, en de zouten, esters en amiden daarvan.Preferred examples of anti-bone mineral resorption bischromones are represented by the formula 1 wherein R1, R2, R3, R4, Rg and Rg are hydrogen, halogen (chlorine, bromine or iodine) lower alkyl (preferably alkyl with 1 -4 carbon atoms) hydroxy or lower alkoxy (preferably alkoxy with 1-4 carbon atoms) 35, and X straight or branched polymethylene with 3-7 carbon- 80 04 90 4 8 atoms including -CH ^ -CH ^ CH -CH ^ -, -CH2 ~ CH2-0-CH2-CH2-, -CE ^ -CO-CB ^ -, -CH2 ~ (o-Ph) -CH2, where o-Ph is 1,2-phenylene, - CH 2 -C (CH 2 OH) (CH 2 Cl) -CH 2 -, -CH 2 -CH (OH) -CH 2 -, or -CH 2 -CH (0H) -CH 2 -O-CH 2 -CH (OH) -CH 2 -, and the salts, esters and amides thereof.
5 Bijzondere voorkeur hebben DNCG en overeenkom stige andere zouten en esters (Amerikaans octrooischrift 3.419.578).Particular preference is given to DNCG and corresponding other salts and esters (US Pat. No. 3,419,578).
Voorbeelden van oxamaten met anti-botmineraal resorptiewerking die de voorkeur hebben zijn de met de formule 2 weergegeven oxanilinezuurderivaten en de met de formule 3 weergege-10 ven fenyleendioxamidezuurderivaten waarin één van de symbolen R,, R., R en R, waterstof of cyaan voorstelt, een tweede en een j 4 5 o derde van voornoemde symbolen waterstof, nitro, amino, halogeen (fluor, chloor, broom, jood), alkyl (bij voorkeur alkyl met 1-4 koolstofatomen), hydroxy, alkoxy (bij voorkeur alkoxy met 1-4 kool- 15 stofatomen) of trifluormethyl voorstellen en gelijk of verschillend kunnen zijn, en de overige symbolen waterstof voorstellen.Preferred examples of oxamates having an anti-bone mineral resorption action are the oxanilic acid derivatives represented by the formula II and the phenylene dioxamic acid derivatives represented by the formula 3 wherein one of the symbols R, R, R and R represents hydrogen or cyano , a second and a third of the above-mentioned symbols hydrogen, nitro, amino, halogen (fluorine, chlorine, bromine, iodine), alkyl (preferably alkyl with 1-4 carbon atoms), hydroxy, alkoxy (preferably alkoxy with 1-4 carbon atoms) or trifluoromethyl and may be the same or different, and the remaining symbols represent hydrogen.
In het onderstaande zijn de resultaten vermeld van een onderzoek naar de remmende werking van lodoxamide (als het dubbelzout van N,N'-(2-chloor-5-cyano-m-fenyleen)dioxamidezuur en 20 tris(hydroxymethyl)aminomethaan) op de calcium-afgifte uit foetaal rattebot met en zonder parathyreoide hormoon als stimulant op de calciumafgifte. Het onderzoek werd uitgevoerd volgens de methode beschreven door Horton, J.E. et al. in Science 199:1342-1345 (1978).Listed below are the results of a study of the inhibitory activity of lodoxamide (as the double salt of N, N '- (2-chloro-5-cyano-m-phenylene) dioxamic acid and 20 tris (hydroxymethyl) aminomethane) on the calcium release from fetal rat bone with and without parathyroid hormone as a stimulant of calcium release. The study was conducted according to the method described by Horton, J.E. et al. in Science 199: 1342-1345 (1978).
4545
Het afgegeven calcium was radio-actief gemerkt Ca en werd bepaald 25 door vloeistofscintillatie spectrometrie. De toegevoegde hoeveelheid parathyreoide hormoon bedroeg 2 μg/ml en de toegevoegde hoeveelheid lodoxamide 250 yUg/ml. De resultaten zijn samengevat in onderstaande tabel A. Daaruit blijkt dat het oxamaat een statistisch significante vermindering in de afgifte van radio-actief calcium bewerkstelligt. 30 In onderstaande tabel B is de calciumafgifte in afhankelijkheid van de hoeveelheid in het medium aanwezig oxamaat over een periode van 120 uren aangegeven. Voor zover in het medium aanwezig bedraagt de hoeveelheid parathyreoide hormoon weer 2 jig/tal.The calcium released was radiolabeled Ca and was determined by liquid scintillation spectrometry. The amount of parathyroid hormone added was 2 µg / ml and the amount of lodoxamide added was 250 µg / ml. The results are summarized in Table A below. It shows that the oxamate effects a statistically significant reduction in the release of radioactive calcium. Table B below shows the calcium release depending on the amount of oxamate present in the medium over a period of 120 hours. If present in the medium, the amount of parathyroid hormone is again 2 µg / tal.
35 8004904 45 935 8004 904 45 9
TABEL ATABLE A
Parathyreolde hormoon Lodoxamide Gemiddelde Ca afgifte, %,over periodes van 0-48 uren 49-120 urenParathyroid hormone Lodoxamide Average Ca release,%, over periods of 0-48 hours 49-120 hours
Afwezig aanwezig in de 11,64 3,63 periode van 0-48 urenAbsent in the 11.64, 3.63 period of 0-48 hours
Aanwezig 29,04 41,49Present 29.04 41.49
Afwezig aanwezig in de 8,95 1,99 periode van 49-120 urenAbsent in the 8.95 1.99 period of 49-120 hours
Aanwezig 36,77 26,98Present 36.77 26.98
Afwezig afwezig 10,03 3,82Absent absent 10.03 3.82
Aanwezig 37,93 37,64Present 37.93 37.64
TABEL BTABLE B
4545
Hoeveelheid Gemiddelde -Ca afgifte, % lodoxamxde, g/ml Zonder parathyreolde Met parathyreoide hormoon hormoon 250 7,11 42,64 100 8,62 40,86 50 8,50 53,87 10 9,89 64,31 1 9,05 74,51 geen 8,71 77,44 80 0 4 90 4Amount Average -Ca release,% lodoxamxde, g / ml Without parathyreolde With parathyroid hormone hormone 250 7.11 42.64 100 8.62 40.86 50 8.50 53.87 10 9.89 64.31 1 9.05 74.51 none 8.71 77.44 80 0 4 90 4
Claims (11)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7339879A | 1979-09-07 | 1979-09-07 | |
| US7340079A | 1979-09-07 | 1979-09-07 | |
| US7339879 | 1979-09-07 | ||
| US7340079 | 1979-09-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8004904A true NL8004904A (en) | 1981-03-10 |
Family
ID=26754428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8004904A NL8004904A (en) | 1979-09-07 | 1980-08-29 | MEDICINE AGAINST BONE MINERAL RESORPTION. |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5649317A (en) |
| AU (1) | AU532512B2 (en) |
| BE (1) | BE885113A (en) |
| DE (1) | DE3033545A1 (en) |
| FR (1) | FR2464716B1 (en) |
| GB (1) | GB2058564B (en) |
| IT (1) | IT1174303B (en) |
| NL (1) | NL8004904A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111602630A (en) * | 2020-06-24 | 2020-09-01 | 山西农业大学 | Establishment of a model for mechanical injury of small intestine of broiler chickens induced by DON |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4764334A (en) * | 1983-10-17 | 1988-08-16 | Westinghouse Electric Corp. | Visual inspection system for radioactive fuel assemblies using fiberoptics |
| US4997824A (en) * | 1987-07-22 | 1991-03-05 | Teva Pharmaceutical Industries Ltd. | Combination of cholecalciferol derivatives for the treatment of renal bone disease |
| US4911931A (en) * | 1987-08-03 | 1990-03-27 | Baylink David J | Pharmaceutical combination for treatment of bone-wasting diseases |
| US5013728A (en) * | 1990-05-04 | 1991-05-07 | Colgate - Palmolive Company | Composition for treating osteoporosis and hormonal imbalance |
| US6037339A (en) * | 1993-02-08 | 2000-03-14 | Akzo Nobel N.V. | C-11 substituted steroids for treating menopausal complaints |
| ZA94715B (en) * | 1993-02-08 | 1994-10-24 | Akzo Nv | Steroids for treating menopausal complaints |
| US5710144A (en) * | 1993-02-08 | 1998-01-20 | Akzo Nobel N.V. | C-11 substituted steroids for treating menopausal complaints |
| WO1998017267A1 (en) * | 1996-10-23 | 1998-04-30 | Zymogenetics, Inc. | Compositions and methods for treating bone deficit conditions |
| DE19832169A1 (en) * | 1998-07-17 | 2000-01-27 | Jenapharm Gmbh | Treating or preventing oral atrophic symptoms, e.g. marginal periodontal disease, by local administration of estrogen such as estriol |
| DE60023122T2 (en) | 1998-10-30 | 2006-07-13 | Rj Innovation | A method for preventing hypocalcaemia in ewes and compositions used therefor |
| AU4825200A (en) * | 1999-05-07 | 2000-11-21 | Board Of Regents, The University Of Texas System | Oral steroidal hormone compositions and methods of use |
| MXPA05014091A (en) * | 2005-12-20 | 2007-06-20 | Leopoldo De Jesus Espinosa Abdala | Pharmaceutical compositions containing synthetic steroid derivatives such as tibolone, minerals such as calcium and the active metabolite of vitamin d (calcitrol) for the prevention and treatment of osteoporosis and menopause. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1473318A (en) * | 1973-05-25 | 1977-05-11 | Fisons Ltd | Solution of 1,3-bis-2-carboxychromon-5-yloxy-propan-2-ol or salts thereof |
| US4029761A (en) * | 1974-10-19 | 1977-06-14 | Fisons Limited | Method for treating gingivitis |
| IL48360A (en) * | 1974-11-09 | 1978-12-17 | Fisons Ltd | Pharmaceutical compositions for the treatment of aphthous stomatitis comprising 1,3-bis-(2-carboxychromon-5-yloxy)-2-carboxychromon-5-yloxy)-2-hydroxypropane |
-
1980
- 1980-08-28 AU AU61843/80A patent/AU532512B2/en not_active Ceased
- 1980-08-29 NL NL8004904A patent/NL8004904A/en not_active Application Discontinuation
- 1980-09-05 BE BE0/202008A patent/BE885113A/en not_active IP Right Cessation
- 1980-09-05 FR FR8019237A patent/FR2464716B1/en not_active Expired
- 1980-09-05 GB GB8028763A patent/GB2058564B/en not_active Expired
- 1980-09-05 IT IT49625/80A patent/IT1174303B/en active
- 1980-09-05 DE DE19803033545 patent/DE3033545A1/en not_active Withdrawn
- 1980-09-08 JP JP12448280A patent/JPS5649317A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111602630A (en) * | 2020-06-24 | 2020-09-01 | 山西农业大学 | Establishment of a model for mechanical injury of small intestine of broiler chickens induced by DON |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2464716A1 (en) | 1981-03-20 |
| AU6184380A (en) | 1981-03-12 |
| IT1174303B (en) | 1987-07-01 |
| BE885113A (en) | 1981-03-05 |
| DE3033545A1 (en) | 1981-04-02 |
| FR2464716B1 (en) | 1985-10-25 |
| JPS5649317A (en) | 1981-05-02 |
| AU532512B2 (en) | 1983-10-06 |
| GB2058564A (en) | 1981-04-15 |
| GB2058564B (en) | 1983-10-26 |
| IT8049625A0 (en) | 1980-09-05 |
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