TOPICAL APPLICATION OF STATINS FOR OSTEOPOROSIS

最近发现洛伐他汀和其他他汀类药物在啮齿类动物中全身和局部刺激骨形成。然而，口服给药后，其局部作用远比其对骨的全身作用显著。这对应于它们的血浆浓度，在一次口服给药后仅短暂升高数小时。他汀类药物在肝脏中被细胞色素P450酶代谢为无活性代谢物。我们认为，他汀类药物到达松质骨表面的浓度，刺激骨形成，他们需要绕过肝脏。我们发现，经皮给药的洛伐他汀导致更高和更持久的血药浓度，并假设这是由一个优越的非肝外周组织，如骨上级药理作用。在本I期申请中，我们计划使用局部给予洛伐他汀的大鼠证实这一点，并将其效果与口服给药进行比较。如果证实局部应用对骨产生更好的作用，则随后的II期应用将针对检查洛伐他汀的最佳局部给药形式以及对全身毒性作用的数据。（洛伐他汀在未来两年内将作为降胆固醇药物获得专利。OsteoScreen有一项他汀类药物作为骨活性药物的专利申请正在申请中。）拟议的商业应用：我们计划确定洛伐他汀作为骨质疏松症合成代谢药物经皮给药的潜力。我们的数据表明，这种递送途径可能导致他汀类药物对骨的药理作用增强。

Lovastatin and other statins have recently been found to stimulate bone formation systemically as well as locally in rodents. However, their effects locally are far more dramatic than their systemic effects on bone following oral administration. This corresponds to their plasma concentrations which following one oral dose are only transiently elevated for several hours. Statins are metabolized by cytochrome P450 enzymes in the liver to inactive metabolites. We propose that for statins to reach cancellous bone surfaces in concentrations that stimulate bone formation, they need to bypass the liver. We have found that transdermal administration of lovastatin leads to higher and more sustained blood levels, and hypothesize that this is paralleled by a superior pharmacologic effect on nonhepatic peripheral tissues such as bone. In this Phase I application, we plan to confirm this using rats to which lovastatin is delivered topically, and compare the effects to oral administration. Should topical application be confirmed to produce better effects on bone, then a subsequent Phase II application will be directed at examining the optimal topical form of delivery of lovastatin, together with data on effects on systemic toxicity. (Lovastatin comes off patent as cholesterol-lowering agent within the next 2 years. OsteoScreen has a pending filed patent application for statins as bone-active agents.) PROPOSED COMMERCIAL APPLICATIONS: We plan to determine the potential for lovastatin administered transdermally as an anabolic agent for osteoporosis. Our data suggests this route of delivery may lead to enhanced pharmacologic effects of the statin on bone.