TOPICAL APPLICATION OF STATINS FOR OSTEOPOROSIS

局部应用他汀类药物治疗骨质疏松症

• 批准号: 6141967
• 负责人: I ROSS GARRETT
• 金额: $ 9.98万
• 依托单位: OSTEOSCREEN, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2000-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6141967
• 关键词: HMG coA reductases; bone density; drug screening /evaluation; laboratory rat; lovastatin; minerals; musculoskeletal disorder therapy; oral administration; osteoporosis; pharmacokinetics; topical drug application

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.

最近发现洛伐他汀和其他他汀类药物可以刺激啮齿动物全身和局部的骨形成。然而，口服给药后，它们的局部作用远比其对骨骼的全身作用更为显着。这对应于其血浆浓度在口服一次剂量后仅在数小时内短暂升高。他汀类药物在肝脏中被细胞色素 P450 酶代谢为无活性的代谢物。我们建议，为了使他汀类药物以刺激骨形成的浓度到达松质骨表面，它们需要绕过肝脏。我们发现洛伐他汀的透皮给药可导致更高且更持续的血液水平，并假设这与对非肝外周组织（例如骨）的优异药理作用相平行。在此一期应用中，我们计划使用局部给予洛伐他汀的大鼠来证实这一点，并比较其与口服给药的效果。如果确认局部应用对骨骼产生更好的效果，那么随后的二期应用将致力于检查洛伐他汀的最佳局部给药形式，以及对全身毒性影响的数据。 （洛伐他汀作为降胆固醇剂的专利将在未来 2 年内到期。OsteoScreen 正在申请他汀类药物作为骨活性剂的专利申请。） 拟议的商业应用：我们计划确定洛伐他汀经皮给药作为骨质疏松症合成代谢剂的潜力。我们的数据表明，这种给药途径可能会增强他汀类药物对骨的药理作用。