雷尼酸鍶性質(zhì)、用途與生產(chǎn)工藝
雷尼酸鍶是一種治療骨質(zhì)疏松癥的藥物，外觀為白色至微黃色粉末或結(jié)晶性粉末，無臭、微溶于水、幾乎不溶于乙醇、易溶于稀鹽酸，由法國Servier公司研制開發(fā)，2004年11月在愛爾蘭首次上市，同年12月在英國上市。日本藤澤制藥公司擁有本品在日本的開發(fā)、生產(chǎn)和銷售權(quán)。臨床上主要用于治療和預(yù)防絕經(jīng)后婦女的骨質(zhì)疏松，顯著降低椎骨骨折及髖骨骨折發(fā)生的危險(xiǎn)。
雷尼酸鍶具有抑制骨吸收，促進(jìn)骨形成的雙重藥理作用。一方面在成骨細(xì)胞富集的細(xì)胞中，能增大膠原蛋白與非膠原蛋白的合成，通過增強(qiáng)前成骨細(xì)胞的增殖而促進(jìn)成骨細(xì)胞介導(dǎo)的骨形成。另一方面，通過降低破骨細(xì)胞分化和再吸收活性，減少骨吸收，從而使得骨更新重新達(dá)到平衡，有利于骨形成。
雷奈酸鍶主要通過鍶原子，發(fā)揮其藥理作用，鍶是一種與鈣同族的堿土金屬元素，在元素周期表中位于鈣的下方。其吸收、分布、排泄與鈣相似?？诜?g以后。鍶的絕對(duì)生物利用度為27％。大劑量的鍶能使骨礦代謝發(fā)生異常，低劑量的鍶能增強(qiáng)前成骨細(xì)胞復(fù)制，增加成骨細(xì)胞的數(shù)量，刺激骨形成；同時(shí)還能降低破骨細(xì)胞的活性，減少破骨細(xì)胞的數(shù)量，降低骨吸收的速率。在動(dòng)物和人體內(nèi)研究也得到的結(jié)果相吻合。
骨質(zhì)疏松癥（OP）是一種進(jìn)行性骨骼疾病，其特征為骨密度（BMD）降低和骨組織顯微結(jié)構(gòu)發(fā)生退行性改變。表現(xiàn)為骨脆性提高和易發(fā)生骨折，后者以脊椎、髖部和腕處最為常見。婦女由于在停經(jīng)后或者接受手術(shù)切除卵巢后，體內(nèi)停止產(chǎn)生能保持骨質(zhì)強(qiáng)硬的雌激素。因此，原發(fā)性O(shè)P在停經(jīng)后或更年期婦女中尤為多見。
目前常用于治療骨質(zhì)疏松的藥物有兩類：一類為抑制破骨細(xì)胞活性從而抑制骨吸收的藥物，如二膦酸鹽、雌激素、降鈣素等；第二類為促進(jìn)成骨細(xì)胞活性從而刺激骨形成的藥物，目前僅有人重組甲狀旁腺素1-34一個(gè)產(chǎn)品上市，需要注射給藥，藥價(jià)較高。
Strontium Ranelate 是Ranelic acid的鍶（II）鹽，用于(-)-Desmethoxyverapamil結(jié)合到鈣離子通道，IC50為0.5 mM。
| Target | Value |
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Calcium channel
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0.5 mM
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Strontium Ranelate (0.1-1 mM; 22 days; Mouse calvaria cells) treatment shows the expression of mRNA for early osteoblast markers (alkaline phosphatase, ALP) is visualized by day 5, while late markers (osteocalcin, OCN) are detectable only by day 15 and beyond.
Strontium Ranelate (0.1-1 mM; 22 days; Mouse calvaria cells) treatment results in significantly increases the mRNA expression of the osteoblastic markers ALP, BSP and OCN at day 22 of MC cell culture.
Strontium Ranelate is found to increase alkaline phosphatase activity and prostaglandin E2 production in a COX-2 dependent manner in murine marrow stromal cells.
RT-PCR
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Cell Line:
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Mouse calvaria (MC) cells
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Concentration:
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0.1 mM, 0.3 mM or 1 mM
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Incubation Time:
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22 days
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Result:
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The expression of mRNA for early osteoblast markers (ALP) was visualized by day 5, while late markers (OCN) were detectable only by day 15 and beyond.
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Western Blot Analysis
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Cell Line:
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Mouse calvaria (MC) cells
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Concentration:
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0.1 mM, 0.3 mM or 1 mM
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Incubation Time:
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22 days
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Result:
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Significantly increased the mRNA expression of the osteoblastic markers ALP, BSP and OCN at day 22 of MC cell culture.
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Strontium Ranelate increases bone formation and decreased bone resorption, which results in increased bone mass in the vertebrae of intact adult mice.
In intact adult rats, Strontium Ranelate also increases bone mass, as measured by dual-energy X-ray absorptiometry, in lumbar vertebra and femur, and this is confirmed by histological assessment of trabecular bone volume in the tibial metaphysis.
Strontium Ranelate is found to decrease bone resorption and to increase bone formation in alveolar bone in normal adult monkeys (Macaca fascicularis), which exhibits extensive bone remodeling.
In ovariectomized rats, short-term (3 months) treatment with Strontium Ranelate prevents trabecular bone loss induced by oestrogen deficiency, as demonstrated by bone ash, bone mineral content and histomorphometric analysis in the tibial metaphysis. This effect results from decreased bone resorption while bone formation was maintained. These beneficial effects of Strontium Ranelate on bone mass and microarchitecture in ovariectomized rats are confirmed in long-term experiments. In this long-term study (2 years), the increase in bone mass and microarchitecture induced by Strontium Ranelate results in a marked improvement in bone strength, supporting the beneficial effect of this drug on bone resistance.
用途
主要用于治療和預(yù)防絕經(jīng)后婦女的骨質(zhì)疏松，顯著降低椎骨骨折及髖骨骨折發(fā)生的危險(xiǎn)。
雷尼酸鍶
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