JP2005060303A - Agent for treating or preventing osteoporosis caused by immobility - Google Patents
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Abstract
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本発明は、ゲラニルアセトンまたはその類似体を有効成分とする不動性骨粗鬆症の治療または予防剤に関するものである。 The present invention relates to a therapeutic or prophylactic agent for immobile osteoporosis containing geranylacetone or an analog thereof as an active ingredient.
骨粗鬆症は骨を形成する骨芽細胞と骨を吸収、破壊する破骨細胞の代謝バランスが崩れ、骨形成の抑制や骨破壊、吸収の進行により骨密度が減少することで起こる。その原因としては加齢や閉経などに伴うホルモン（エストロゲン）の変化や、寝たきりなどの運動不足状態、また、ダイエットなどによるカルシウム不足などが挙げられる。 Osteoporosis is caused by the metabolic balance between osteoblasts that form bone and osteoclasts that absorb and destroy bone, and bone density decreases due to inhibition of bone formation and progression of bone destruction and resorption. The causes include changes in hormones (estrogens) associated with aging and menopause, lack of exercise such as bedridden, and calcium deficiency due to diet and the like.
エストロゲン欠乏に由来する骨粗鬆症の詳細な発症機序は不明であるが、エストロゲン低下により破骨細胞の活性化が起こり、骨代謝が活発化し、骨形成を上回る骨吸収の亢進が起こる結果、骨量が低下することが報告されている。この状態に対して、エストロゲン等の女性ホルモンを投与すると、骨吸収が抑制され、それに伴い骨形成も抑制されることにより、平常の骨代謝を示すようになる。 Although the detailed pathogenesis of osteoporosis resulting from estrogen deficiency is unknown, osteoclast activation occurs due to decreased estrogen, bone metabolism is activated, and bone resorption is accelerated beyond bone formation. Has been reported to decrease. When a female hormone such as estrogen is administered to this state, bone resorption is suppressed, and bone formation is also suppressed accordingly, thereby showing normal bone metabolism.
一方で、寝たきりやギプス固定などによる骨粗鬆症は不動性骨粗鬆症と呼ばれ、荷重の低下や関節の固定によって骨に加えられるメカニカルストレスが低下することによる。
骨組織は骨に加えられたメカニカルストレスを受容し、骨代謝を行う。従って骨に加えられるメカニカルストレスが低下すると骨代謝は骨形成が低下し、骨吸収が亢進されるように進み、骨の退化が起こる。
これは関節リウマチや神経疾患、また長期間無重力状態におかれ、メカニカルストレスが低下する宇宙飛行士の骨量減少にも関連している。
On the other hand, osteoporosis due to bedridden or cast fixation is called immobility osteoporosis, and is due to a decrease in mechanical stress applied to bone due to a decrease in load or joint fixation.
Bone tissue receives mechanical stress applied to bone and performs bone metabolism. Therefore, when the mechanical stress applied to the bone decreases, the bone metabolism progresses so that bone formation decreases, bone resorption is increased, and bone degeneration occurs.
This is also associated with rheumatoid arthritis, neurological disease, and bone loss in astronauts who have been in zero gravity for long periods of time and have reduced mechanical stress.
現在、日本における骨粗鬆症の患者は、800万人〜1000万人と推定され、大腿骨頸部骨折は年間約9万人と急速に増加しており、様々な治療方法や予防剤が開発されている。
骨粗鬆症の予防剤としては、血液中のカルシウム量を維持し、骨吸収作用を抑制するカルシウム製剤やカルシウムの吸収を促進し、血液中のカルシウム量を保つビタミンＤ製剤、骨吸収を抑制し、カルシウムを骨に運ぶカルシトニンの分泌とカルシウムの吸収、ビタミンＤの活性化を促進するエストロゲン製剤、骨吸収を直接抑制し、カルシトニンの分泌を促進して骨吸収を抑制し、また破骨細胞の形成を阻害するイソフラボン誘導体、骨芽細胞に直接作用して、骨量を増加させ、また骨吸収抑制作用も有するビタミンK2、破骨細胞を減少させて骨吸収を抑制し、骨芽細胞の骨形成を促進するカルシトニン製剤、破骨細胞の増殖を抑え、さらにその働きを抑えるビスホスホネ−ト系骨代謝改善剤等がある。
Currently, there are an estimated 8 million to 10 million osteoporosis patients in Japan, and the number of femoral neck fractures is rapidly increasing to about 90,000 per year. Various treatment methods and preventive agents have been developed. Yes.
As a preventive agent for osteoporosis, calcium preparations that maintain the amount of calcium in the blood and suppress bone resorption action and vitamin D preparations that promote calcium absorption and keep calcium in the blood, bone resorption is suppressed, calcium Estrogen preparation that promotes the secretion of calcium and calcium absorption, vitamin D activation to carry bone into the bone, directly inhibits bone resorption, suppresses bone resorption by promoting secretion of calcitonin, and also forms osteoclasts Inhibiting isoflavone derivative, which acts directly on osteoblasts to increase bone mass and also suppresses bone resorption, vitamin K 2 , reduces osteoclasts and suppresses bone resorption, osteoblast bone formation There are calcitonin preparations that promote bisphosphonates, bisphosphonate bone metabolism improving agents that suppress the growth of osteoclasts and further suppress their action.
これらの予防剤を用いた薬物療法は骨粗鬆症の治療の中心的な治療方法として用いられている。一方で服用の仕方によっては、カルシウムとキレートをつくり、かえって吸収を抑制してしまう場合や、高カルシウム血症を起こす場合もある。また、長期の服用で尿路結石が生じたり、悪心、嘔吐、食欲不振、皮膚の発疹、嚥下困難、嚥下痛、下痢、軟便などの様々な副作用が生じたりするなど、服用には注意が必要とされ、管理が難しい場合もある。従って、副作用等の心配がなく、安全で効果的な予防剤が求められる。 Drug therapy using these prophylactic agents is used as a central treatment method for the treatment of osteoporosis. On the other hand, depending on how you take it, you may make a chelate with calcium and suppress the absorption or cause hypercalcemia. In addition, urinary stones may occur in long-term use, and various side effects such as nausea, vomiting, loss of appetite, skin rash, difficulty swallowing, swallowing pain, diarrhea, loose stool, etc. may be required. It can be difficult to manage. Therefore, there is a need for a safe and effective prophylactic agent without worrying about side effects.
本発明者らは、これらの予防剤のうち、骨芽細胞に直接作用しかつ骨吸収抑制作用を有するとともに、比較的副作用の少ないビタミンK2に着目した。ビタミンK2（以下、メナテトレノンという）は、その化学構造のうち側鎖であるゲラニルゲラニル基により、骨吸収抑制作用を示すことが報告されている（非特許文献１）。従ってこれと同様の構造を有するゲラニルゲラニルアセトン（テプレノン、以下、GGAという）やその類似体も骨吸収抑制作用を有し、骨粗鬆症の予防剤として利用できる可能性があると考えた。 Among these preventive agents, the present inventors have focused on vitamin K 2 which acts directly on osteoblasts and has an action of suppressing bone resorption and has relatively few side effects. Vitamin K 2 (hereinafter referred to as menatetrenone) has been reported to exhibit a bone resorption inhibitory action due to a geranylgeranyl group which is a side chain in its chemical structure (Non-patent Document 1). Therefore, it was considered that geranylgeranylacetone (teprenone, hereinafter referred to as GGA) and its analogs having the same structure also have a bone resorption suppressing action and may be used as a preventive agent for osteoporosis.
GGAはエーザイ株式会社によって開発され、胃粘液増加作用、胃粘膜の保護・修復を促進し、安全性の高い胃粘膜保護剤として、胃潰瘍の治療などに広く臨床で使用されている。また、皮膚などにおけるメラニン生成を抑制し、シミ、ソバカス等を改善する美白剤や美白用組成物として有用である（特許文献1）。
骨粗鬆症の予防剤として有用であれば、薬価も安く、副作用によりビスホスホネート系骨代謝改善剤が服用困難な症例や食道粘膜に問題のある膠原病患者、高齢者や小児にも安心して処方が可能となる。
GGA was developed by Eisai Co., Ltd. and promotes gastric mucus increasing action, gastric mucosa protection and repair, and is widely used clinically as a highly safe gastric mucosa protective agent for the treatment of gastric ulcers. Further, it is useful as a whitening agent or a whitening composition that suppresses melanin production in the skin and the like and improves spots, freckles, etc. (Patent Document 1).
If it is useful as a prophylactic agent for osteoporosis, the drug price is low, and it can be prescribed with peace of mind for patients who have difficulty taking bisphosphonate bone metabolism improving agents due to side effects, patients with collagen disease who have problems with the esophageal mucosa, elderly people and children. Become.
本発明者らはGGA及びその類似体についてエストロゲン欠乏由来の骨粗鬆症の治療又は予防効果を調べたところ骨粗鬆症の予防剤としての作用がみられた。そこで、エストロゲン欠乏による骨粗鬆症とは、その発症機序が異なる不動性骨粗鬆症についても同様の治療又は予防効果があるのではないかと着想し、実験を繰り返したところ、GGAは不動性骨粗
鬆症においても治療又は予防能力を有することを見出し、本発明を完成するに至った。
The inventors of the present invention have examined the effect of osteoporosis derived from estrogen deficiency on GGA and its analogs, and found to have an action as a preventive agent for osteoporosis. Therefore, the idea of osteoporosis due to estrogen deficiency is that there is a similar treatment or prevention effect for immobility osteoporosis whose onset mechanism is different, and repeated experiments, GGA is also treated in immobility osteoporosis or It has been found that it has preventive ability, and the present invention has been completed.
GGAは分子式C23H38O、分子量330.55で末端にメチル基を有する。無色から微黄色透明の油状の液体で、わずかに特異なにおいがあり、味はない。水には溶けず、メタノール、エタノール、アセトン、クロロホルム又はヘキサンに混和する。沸点は160〜185℃である。効能効果は急性胃炎、慢性胃炎、胃潰瘍の胃粘膜病変（びらん、出血、発赤、浮腫）の改善がよく知られている。
GGAおよびメナテトレノンの化学構造式を図１に示した。
The chemical structural formulas of GGA and menatetrenone are shown in FIG.
本発明は、不動性骨粗鬆症において副作用の少ない安全、安価かつ治療又は予防効果の高い不動性骨粗鬆症の治療または予防剤の提供を課題とする。特に副作用のため他の骨粗鬆症予防剤が服用困難な症例や食道粘膜に問題のある膠原病患者、高齢者や小児にも安心して投与が可能で、不動性骨粗鬆症に有用な治療または予防剤のひとつになる可能性が大である。 An object of the present invention is to provide a therapeutic or preventive agent for immobile osteoporosis that is safe, inexpensive, and has a high therapeutic or prophylactic effect with few side effects in immobile osteoporosis. One of the useful treatments or preventive agents for immobile osteoporosis, which can be safely administered to patients with collagen disease, elderly people and children who have difficulty with other osteoporosis preventive agents due to side effects, and those with esophageal mucosa problems. Is likely to become.
本発明はGGAおよびその類似体がゲラニルゲラニル基を有するメナテトレノンと同様の破骨細胞形成抑制能を薬理濃度で有するかを調べ、in vivo，in vitroにおいて不動性骨粗鬆症への治療または予防剤としての用途を見出した。 The present invention investigates whether GGA and its analogs have the same osteoclastogenesis inhibitory ability as menatetrenone having a geranylgeranyl group at a pharmacological concentration, and use as a therapeutic or preventive agent for immobile osteoporosis in vivo and in vitro I found.
すなわち、本発明は、次のとおり不動性骨粗鬆の治療または予防剤に関する。
1. GGAまたはその類似体を有効成分とする不動性骨粗鬆の治療または予防剤
2．経口製剤である前記１に記載の不動性骨粗鬆の治療または予防剤
3．GGAを30〜200mg含有する１または２に記載の不動性骨粗鬆の治療または予防剤
4. ゲラニルゲラニルアセトンまたはその類似体を有効成分とするメバロチン代謝経路においてゲラニルゲラニルピロリン酸と拮抗作用を示す拮抗剤
That is, the present invention relates to an agent for treating or preventing immobility osteoporosis as follows.
1. A therapeutic or prophylactic agent for immobile osteoporosis containing GGA or an analog thereof as an active ingredient
2． 2. The therapeutic or prophylactic agent for immobile osteoporosis according to 1 above, which is an oral preparation
3． The therapeutic or preventive agent for immobile osteoporosis according to 1 or 2, containing 30 to 200 mg of GGA
4. Antagonists that antagonize geranylgeranyl pyrophosphate in the mevalotin metabolic pathway with geranylgeranylacetone or its analogs as active ingredients
本発明におけるGGAの類似体にはGGAの１位のメチル基を低級アルキル基、例えばエチル基、プロピル基、イソプロピル基、ブチル基、s‐ブチル基、t-ブチル基等によって置換したものがある。これらの化合物は、通常のアルキル置換によって得ることができる。
本発明の不動性骨粗鬆の治療または予防剤は経口製剤として用いることが望ましい。経口製剤としては、薬理学上許容される担体、賦形剤、希釈剤、増量剤、崩壊剤、安定剤、その他の添加物と混合し、錠剤、散剤、顆粒剤、カプセル剤、丸剤、トローチ剤等とするとよい。また、乳剤やシロップ剤のような形態によるとよい。また従来知られているゲラニルゲラニルアセトンの胃粘膜保護剤胃潰瘍治療剤を本発明の目的のために転用してもよい。
投与量は疾患の種類、程度、患者の年齢、性別、体重によって変わるが通常成人一人あたり100〜200mg、好ましくは150mgを1日数回に分けて服用することが好ましい。この点から製剤としてはGGAまたはその類似体を一錠（あるいは１カプセル）中に30〜200mg含有することが好ましい。
The GGA analogs in the present invention include those in which the methyl group at the 1-position of GGA is substituted with a lower alkyl group such as an ethyl group, a propyl group, an isopropyl group, a butyl group, a s-butyl group, or a t-butyl group. . These compounds can be obtained by conventional alkyl substitution.
The therapeutic or preventive agent for immobile osteoporosis of the present invention is desirably used as an oral preparation. Oral preparations are mixed with pharmacologically acceptable carriers, excipients, diluents, bulking agents, disintegrants, stabilizers, other additives, tablets, powders, granules, capsules, pills, A lozenge is recommended. Further, it may be in the form of an emulsion or syrup. Further, a conventionally known geranylgeranylacetone gastric mucosa protective agent for treating gastric ulcer may be used for the purpose of the present invention.
The dose varies depending on the type and degree of the disease, the age, sex and weight of the patient, but it is usually preferable to take 100 to 200 mg, preferably 150 mg per adult, in several divided doses per day. In this respect, the preparation preferably contains 30 to 200 mg of GGA or an analog thereof in one tablet (or one capsule).
本発明のGGAおよびその類似体は副作用の少ない安全、安価かつ効果的な不動性骨粗鬆症の治療または予防剤として利用できる。特に副作用により他の骨粗鬆症予防剤が服用困難な症例や食道粘膜に問題のある膠原病患者、高齢者や小児にも安心して処方が可能で、不動性骨粗鬆症に有用な治療または予防剤として利用できる。 The GGA of the present invention and analogs thereof can be used as a safe, inexpensive and effective agent for treating or preventing immobility osteoporosis with few side effects. It can be used as a useful treatment or prevention agent for immobile osteoporosis because it can be prescribed for patients with collagen disease, elderly people and children who have difficulty taking other osteoporosis preventive agents due to side effects, and those with esophageal mucosa problems. .
骨粗鬆症は骨代謝において破骨細胞の活性化が進み、骨吸収が亢進することにより起こる。従って、GGAが破骨細胞の活性化を薬理濃度で抑制できれば、骨粗鬆症の治療または予防剤として有用であるといえる。
そこで本発明者らは、GGAおよびその類似体を用い、ゲラニルゲラニル基を有するメナテトレノンと同様の破骨細胞形成抑制能を薬理濃度で有するかを調べた。
Osteoporosis is caused by increased osteoclast activation in bone metabolism and increased bone resorption. Therefore, if GGA can suppress the activation of osteoclasts at a pharmacological concentration, it can be said that it is useful as a therapeutic or preventive agent for osteoporosis.
Therefore, the present inventors examined whether osteoclast formation inhibitory ability similar to menatetrenone having a geranylgeranyl group was used at a pharmacological concentration using GGA and its analogs.
ヒト末梢血より取り出した破骨前駆細胞を用い、破骨細胞形成を誘導する系においてGGAの破骨細胞形成抑制作用を検討した。また、ヒト成熟破骨細胞に対する骨吸収抑制作用を検討した。
また、本発明者らはGGAの骨吸収抑制作用は破骨細胞の機能発現に関わるメバロン酸代謝経路において、GGAがGGPP(ゲラニルゲラニルピロリン酸）と拮抗することによるのではないかと考え、成熟破骨細胞に対するGGAとGGPPの拮抗的作用を検討した。さらに不動性骨粗鬆症モデル動物に対し、GGAを投与し骨密度の改善を検討した。
以下、実施例をあげて本発明をさらに詳細に説明するが、本発明は、何らこれらに限定されるものではない。
Using osteoclast progenitor cells extracted from human peripheral blood, we investigated the inhibitory effect of GGA on osteoclast formation in a system that induces osteoclast formation. Moreover, the bone resorption inhibitory effect with respect to a human mature osteoclast was examined.
Further, the present inventors considered that GGA's bone resorption inhibitory effect may be due to GGA antagonizing GGPP (geranylgeranyl pyrophosphate) in the mevalonate metabolic pathway involved in the functional expression of osteoclasts. The antagonistic effect of GGA and GGPP on cells was examined. Furthermore, GGA was administered to immobility osteoporosis model animals, and the improvement of bone density was examined.
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these at all.
1. ヒト破骨細胞の形成と同定
健常者末梢血より単各球を分離しM-CSF(マクロファージコロニー刺激因子、100ng/ml)存在下で72時間培養し、非付着培養を除き、実施例で用いるヒト前駆破骨細胞を得た。これに、破骨細胞形成を誘導するヒト可溶化RANKL(receptor activator of NF-κBLigand：NF-κB活性化受容体リガンド、100ng/ml)とM-CSF（100ng/ml）とともにメナトレン（0、10-8、10-7、10-6M）とGGA（0、100、250、500、1000ng/ml）をそれぞれ各濃度加え、培養を行った。
1. Formation and identification of human osteoclasts Monocytes were isolated from peripheral blood of healthy individuals and cultured for 72 hours in the presence of M-CSF (macrophage colony stimulating factor, 100 ng / ml). Human progenitor osteoclasts used in 1 were obtained. This includes menatrene (0, 10) with human solubilized RANKL (receptor activator of NF-κBLigand: NF-κB activating receptor ligand, 100 ng / ml) and M-CSF (100 ng / ml) to induce osteoclastogenesis. -8 , 10 -7 , 10 -6 M) and GGA (0, 100, 250, 500, 1000 ng / ml) were added at respective concentrations, and culture was performed.
培養10日後に形成された多核細胞に抗ビトロネクチンレセプター及び抗CD51抗体または抗CD11b抗体を加え、免疫染色を行った。また蛍光micro-beadsの貪食能を検討した。また骨吸収活性はdentine slice上の破骨細胞を48時間培養し、ヘマトキシン染色により吸収窩を測定した。
図２に示すように、ヒト可溶化RANKLのみを添加した培地で形成された多核細胞はCD51陽性、CD11b陰性で貪食能がなく、dentine sliceに吸収窩を形成し、osteoprotegerinの添加により形成は完全に抑制され、破骨細胞としての形質と機能を示した。
一方でメナトレンを添加した培地では可溶性RANKLの存在下で10-7〜10-6Mの薬理濃度にて濃度依存的に破骨細胞形成抑制を示した。
また図３に示すように、GGAも同様に500〜1000ng/ml(1.5〜3.3×10-6M)の薬理的濃度にて濃度依存的にヒトの骨細胞形成を抑制した。よってGGAは破骨細胞の分化抑制作用を有するといえる。
Anti-vitronectin receptor and anti-CD51 antibody or anti-CD11b antibody were added to the multinucleated cells formed after 10 days of culture, and immunostaining was performed. We also examined the phagocytic ability of fluorescent micro-beads. Bone resorption activity was determined by culturing osteoclasts on dentine slices for 48 hours and measuring resorption pits by hematoxin staining.
As shown in Fig. 2, multinucleated cells formed in a medium supplemented with only human-solubilized RANKL are CD51 positive, CD11b negative, have no phagocytic ability, form absorption pits in dentine slices, and complete formation by addition of osteoprotegerin It showed the character and function as osteoclast.
On the other hand, in the medium supplemented with menatrene, osteoclast formation was suppressed in a concentration-dependent manner at a pharmacological concentration of 10 −7 to 10 −6 M in the presence of soluble RANKL.
Moreover, as shown in FIG. 3, GGA similarly suppressed human bone cell formation in a concentration-dependent manner at a pharmacological concentration of 500 to 1000 ng / ml (1.5 to 3.3 × 10 −6 M). Therefore, it can be said that GGA has an osteoclast differentiation inhibitory action.
2. GGAのヒト成熟破骨細胞に対する効果
ヒト末梢血単球にヒト可溶化RANKL(100ng/ml）とGGA（0、100、250、500、1000ng/ml）を添加しヒト成熟破骨細胞の形成を誘導した。破骨細胞はin vitroの系において成熟化により細胞辺縁にactin ringを形成する。
rhodamine phalloidin染色によりactin ringの変化を観察したところ、GGA無添加で培養した破骨細胞にはactin ringが観察された（図４A）が、GGAを添加した破骨細胞では変形したactin ringが観察された（図４B）。よってGGAはヒト成熟破骨細胞の形成抑制効果を有するといえる。
2. Effect of GGA on human mature osteoclasts Human solubilized RANKL (100 ng / ml) and GGA (0, 100, 250, 500, 1000 ng / ml) were added to human peripheral blood monocytes. Induced formation. Osteoclasts form an actin ring at the cell edge by maturation in an in vitro system.
When the change of actin ring was observed by rhodamine phalloidin staining, an actin ring was observed in osteoclasts cultured without GGA (Fig. 4A), but a deformed actin ring was observed in osteoclasts added with GGA. (FIG. 4B). Therefore, it can be said that GGA has an effect of suppressing the formation of human mature osteoclasts.
3．GGAとGGPPの拮抗作用
図５に示すように、GGPPはメバロン酸代謝経路において破骨細胞の機能発現に関わる。従ってGGA添加によってactin ringが変形した破骨細胞にGGPPを添加し、actin ringの変形を抑制することが可能であれば、GGAとGGPPは拮抗的作用をしているといえる。
実施例２において、GGA添加によりactin ringが変形した系を用い、GGPPを各濃度(0、1、10μM)添加したところ、図６に示すように、GGPP濃度依存的にactin ring の形状の変化が抑制された。
よってGGAの破骨細胞抑制作用はGGAのメバロン酸代謝経路におけるGGPPと拮抗作用による可能性が示された。
3． Antagonism of GGA and GGPP As shown in FIG. 5, GGPP is involved in the functional expression of osteoclasts in the mevalonate metabolic pathway. Therefore, if GGPP can be added to osteoclasts whose actin ring has been deformed by the addition of GGA and the deformation of the actin ring can be suppressed, it can be said that GGA and GGPP have an antagonistic action.
In Example 2, using a system in which the actin ring was deformed by addition of GGA and adding GGPP at various concentrations (0, 1, 10 μM), the change in the shape of the actin ring depending on the GGPP concentration as shown in FIG. Was suppressed.
Therefore, the osteoclast inhibitory action of GGA may be due to GGPP and antagonism in the mevalonate metabolic pathway of GGA.
4．GGA投与による不動性骨粗鬆症モデル動物の骨密度の変化
不動性骨粗鬆症動物に対し、GGAを薬理濃度投与し、骨密度が改善できればGGAは不動性骨粗鬆症治療及び予防剤として利用できるといえる。
不動性骨粗鬆症モデル動物として、４週目のSprague-Dawlayラット（Japan SLC株式会社）を用い、12時間ごとのlight/darkサイクルのもと餌と水と各濃度（0、100mg/kg）のGGAを毎日継続して５週間与えた。
実施後すべてのラットの大腿骨の骨密度をDXA（Dual Energy X-Ray Absoptiometry）法にて測定し、wilcoxonの順位検定を行ったところ、表１に示すように、GGAを与えたラットは与えなかったラットに比べて１〜２０の全スキャン（ｓ）でP=0.0003と有意に骨密度が高いことが確認された。よってGGAが不動性骨粗鬆症の予防剤として有用であることが示唆された。結果は図7および図８に示した。
Four. Change in bone density of immobility osteoporosis model animal by GGA administration If GGA is administered to a fixed osteoporosis animal by pharmacological concentration and bone density can be improved, GGA can be used as a treatment and prevention agent for immobility osteoporosis.
A 4 week Sprague-Dawlay rat (Japan SLC Co., Ltd.) was used as an immobile osteoporosis model animal, and GGA with food, water and various concentrations (0, 100 mg / kg) under a light / dark cycle every 12 hours. Was given daily for 5 weeks.
After the measurement, bone mineral density of femurs of all rats was measured by DXA (Dual Energy X-Ray Absoptiometry) method and wilcoxon rank test was performed. As shown in Table 1, rats given GGA were given It was confirmed that the bone density was significantly high at P = 0.0003 in all scans (s) of 1 to 20 compared to the rats that did not. Therefore, it was suggested that GGA is useful as a preventive agent for immobile osteoporosis. The results are shown in FIG. 7 and FIG.
5． GGAの骨粗鬆症予防剤
セルベックス（エーザイ株式会社）１カプセル50mgを一日３カプセル、毎食後服用し、骨粗鬆症の治療または予防剤として用いる。
Five. GGA's osteoporosis-preventing agent Selvex (Eisai Co., Ltd.) 1 capsule 50mg is taken 3 times daily after meals and used as a treatment or prevention agent for osteoporosis.
[図２]
a,培養液に可溶化RANKLを100ng/ml添加
b,培養液のみ
c,培養液に可溶化RANKLを100ng/mlとメナテトレノン10-8Ｍ添加
d,培養液に可溶化RANKLを100ng/mlとメナテトレノン10-7Ｍ添加
e,培養液に可溶化RANKLを100ng/mlとメナテトレノン10-6Ｍ添加
[図３]
a,培養液に可溶化RANKLを100ng/ml添加
b,培養液のみ
c,培養液に可溶化RANKLを100ng/mlとGGA 100ng/ml添加
d,培養液に可溶化RANKLを100ng/mlとGGA 250ng/ml添加
e,培養液に可溶化RANKLを100ng/mlとGGA 500ng/ml添加
f,培養液に可溶化RANKLを100ng/mlとGGA 1000ng/ml添加
[図４]
a,培養液のみ
b,培養液にGGAを100ng/ml添加
[図６]
a,培養液のみ
b,培養液にGGA 1000g/ml添加
c,培養液にGGA 1000g/mlとGGPP 1.0μM添加
d,培養液にGGA 1000g/mlとGGPP 10μM添加
[図７]
control:GGAを投与しなかったラット
G1: GGAを投与したラット
[図８]
control:GGAを投与しなかったラット
G1: GGAを投与したラット
[Figure 2]
a, Add 100 ng / ml solubilized RANKL to the culture solution
b, culture medium only
c, and solubilized RANKL 100 ng / ml and menatetrenone 10 -8 M added to the culture medium
d, solubilized RANKL 100 ng / ml and menatetrenone 10 -7 M added to the culture medium
e, solubilized RANKL 100 ng / ml and menatetrenone 10 -6 M added to the culture medium
[Fig. 3]
a, Add 100 ng / ml solubilized RANKL to the culture solution
b, culture medium only
c, Add 100ng / ml solubilized RANKL and 100ng / ml GGA to the culture solution
d, Add 100 ng / ml solubilized RANKL and 250 ng / ml GGA to the culture solution
e, Add 100 ng / ml solubilized RANKL and 500 ng / ml GGA to the culture solution
f, Add 100ng / ml solubilized RANKL and 1000ng / ml GGA to the culture medium
[Fig.4]
a, Culture medium only
b, Add 100 ng / ml GGA to the culture
[Fig. 6]
a, Culture medium only
b, GGA 1000g / ml added to the culture
c, GGA 1000g / ml and GGPP 1.0μM added to the culture
d, GGA 1000g / ml and GGPP 10μM added to the culture solution
[Fig. 7]
control: Rats not receiving GGA
G1: Rats administered GGA
[Fig. 8]
control: Rats not receiving GGA
G1: Rats administered GGA
Claims (4)
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| JP2003292537A JP2005060303A (en) | 2003-08-12 | 2003-08-12 | Agent for treating or preventing osteoporosis caused by immobility |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008038712A1 (en) * | 2006-09-27 | 2008-04-03 | Kumamoto University | Therapeutic/prophylactic agent for metabolic syndrome |
| US9045403B2 (en) | 2012-02-29 | 2015-06-02 | Coyote Pharmaceuticals, Inc. | Geranyl geranyl acetone (GGA) derivatives and compositions thereof |
| US9119808B1 (en) | 2012-10-08 | 2015-09-01 | Coyote Pharmaceuticals, Inc. | Treating neurodegenerative diseases with GGA or a derivative thereof |
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| WO1995033466A1 (en) * | 1994-06-09 | 1995-12-14 | Leiras Oy | Pyridylbisphosphonates for use as a therapeutical agent |
| JPH10338678A (en) * | 1997-06-06 | 1998-12-22 | Takeda Chem Ind Ltd | Azole derivative, its production and use thereof |
| JP2001226265A (en) * | 2000-01-12 | 2001-08-21 | Pfizer Prod Inc | Method for reducing morbidity and/or fatal risk |
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| JP2004026715A (en) * | 2002-06-25 | 2004-01-29 | Sumitomo Pharmaceut Co Ltd | Therapeutic agent for osteoporosis and osteopenia |
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| WO1995033466A1 (en) * | 1994-06-09 | 1995-12-14 | Leiras Oy | Pyridylbisphosphonates for use as a therapeutical agent |
| JPH10338678A (en) * | 1997-06-06 | 1998-12-22 | Takeda Chem Ind Ltd | Azole derivative, its production and use thereof |
| JP2003500453A (en) * | 1999-06-01 | 2003-01-07 | ペプトル・リミテツド | Conformationally constrained backbone cyclized interleukin-6 antagonist |
| JP2001226265A (en) * | 2000-01-12 | 2001-08-21 | Pfizer Prod Inc | Method for reducing morbidity and/or fatal risk |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008038712A1 (en) * | 2006-09-27 | 2008-04-03 | Kumamoto University | Therapeutic/prophylactic agent for metabolic syndrome |
| US9045403B2 (en) | 2012-02-29 | 2015-06-02 | Coyote Pharmaceuticals, Inc. | Geranyl geranyl acetone (GGA) derivatives and compositions thereof |
| US9119808B1 (en) | 2012-10-08 | 2015-09-01 | Coyote Pharmaceuticals, Inc. | Treating neurodegenerative diseases with GGA or a derivative thereof |
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