Application of tadins inhibiting formation of osteoclast

A technology for inhibiting osteoclasts and statins, applied in the direction of active ingredients of esters, bone diseases, organic active ingredients, etc., can solve the problems of no proven atorvastatin

Inactive Publication Date: 2003-03-19
WARNER-LAMBERT CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, none of the above publications demonstrate atorvastatin, or for that matter the therapeutic role of statins in the regulation of osteoclastogenesis and related diseases

Method used

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  • Application of tadins inhibiting formation of osteoclast
  • Application of tadins inhibiting formation of osteoclast
  • Application of tadins inhibiting formation of osteoclast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Bone Marrow Cell Culture

[0063] Osteoclasts were obtained from bone marrow cells of 6- to 8-week-old C57B1 / 6 mice as previously described, Kobayashi K et al., Tumor Necrosis Factorα stimulates osterclast differentiation by a mnechanism independent of the ODF / RANKL-RANK interaction, J. Exp. Med., 2000;191:275-285. Briefly, after aseptically removing the femur, the adhering soft tissue is stripped from the bone. Bone marrow was drained with alpha minimum essential medium (α-MEM) using a syringe and needle. On a 48-well culture plate, culture bone marrow cells (0.15 × 10 6 cells / well) for 3 days. The osteoclasts thus obtained were further cultured for 5 days with RANKL ± atorvastatin, the S,S-enantiomer of atorvastatin or osteosarcoma (OPG). OPG, the lytic decoy receptor of RANKL, has been shown to effectively block RANKL-induced osteoclastogenesis in several in vivo and in vitro models. In some experiments, compounds were added on day 5 after isolation. At the end...

Embodiment 2

[0065] RAW 264.7 cell culture

[0066] RAW cells were cultured in α-MEM containing 10% FBS, 100 IU penicillin, 100 μg / mL streptomycin. Plate at a density of 2000 cells / well on 48-well culture plates. After overnight incubation, they were stimulated with RANKL (50ng / mL) ± atorvastatin, the S, S-enantiomer of atorvastatin or osteosarcoma (OPG) for 5 days, and stained to detect TRAP at the end of 5 days.

Embodiment 3

[0068] Tartrate-resistant acid phosphatase (TRAP) staining

[0069] After an initial wash with 1X PBS, cells were finely fixed for 30 seconds with an acetone-based fixative solution containing acetone, citric acid, and 37% formaldehyde. After washing twice with distilled water preheated to 37°C, the cells were incubated at 37°C in acetate buffer containing naphthol AS-B1 and Fast Garnet GBC solution for 45 minutes. TRAP-positive cells are usually brown when viewed under a microscope. Count the total number of TRP-positive cells with 3 or more nuclei in each well. TRAP activity is a phenotypic hallmark of mature osteoclasts.

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Abstract

A method for inhibiting the formation of osteoclasts comprising administering a therapeutically effective amount of a statin to a mammal in need thereof as well as pharmaceutical compositions, kits for containing such compositions comprising a statin or a method of treating or preventing a disease state selected from the group consisting of osteoporosis, Paget's disease, osteolysis, hypercalcemia of malignancy, osteogenesis imperfecta, osteoarthritis, alveolar bone loss, side effects of immunosuppressive therapy, and side effects of chronic glucocorticoid use by inhibiting the formation of osteoclasts comprising administering a therapeutically effective amount of a statin to a mammal in need thereof.

Description

field of invention [0001] The present invention relates to the application of statins (statins) to inhibit osteoclast formation, more specifically, the present invention relates to the application and pharmaceutical composition of atorvastatin (atorvastatin) to inhibit osteoclast formation, containing the composition containing statin Kit, and method for treating or preventing diseases such as osteoporosis, Paget's disease, osteolysis, hypercalcemia of malignancy, osteogenesis imperfecta by inhibiting osteoclast formation , osteoarthritis, alveolar bone loss and side effects of immunosuppressive therapy and long-term use of glucocorticoids. Background of the invention [0002] Maintenance of bone density is a dynamic process in which osteoclasts resorb bone and osteoblasts remodel bone, Parfitt Am, Riggs BL, Melton LJ, Osteoporosis: etiology, diagnosis and management, New York: Raven Press, 1988;13:501. In conditions such as osteoporosis and Paget'...

Claims

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Application Information

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IPC IPC(8): A61K31/22A61K31/366A61K31/40A61K31/404A61K31/4418A61K31/47A61K31/505A61P19/00A61P19/02A61P19/08A61P19/10A61P43/00
CPCA61K31/47A61K31/366A61K31/505A61K31/4418A61K31/404A61K31/22A61K31/40A61P19/00A61P19/02A61P19/08A61P19/10A61P3/14A61P37/02A61P43/00A61P9/08
Inventor 维杰伊库马·M·巴拉吉雷迪卡·M·德瓦拉雷加布兰登·R·彼得斯理查德·R·伦基维茨
Owner WARNER-LAMBERT CO
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