Competitive Equilibrium-based Displacement of Bisphosphonates as Novel Therapeutic Approach for BRONJ

基于竞争平衡的双膦酸盐置换作为 BRONJ 的新型治疗方法

基本信息

批准号：
8981861
负责人：
Frank H. Ebetino
金额：
$ 15万
依托单位：
BIOVINC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-21 至 2017-08-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8981861
关键词：
Abate Ablation Address Adsorption Affect Affinity American Angiogenesis Inhibitors Animal Model Binding Bioavailable Biology Bone necrosis California Cancer Patient Chemicals Chemistry Clinical Communication Complication Data Dental Dental Care Development Disease Distant Dose Effectiveness Equilibrium Femur Fistula Generations Generic Drugs Gingiva Goals Half-Life Health Health Professional Holidays Hydroxyapatites Image Image Analysis In Vitro Injection of therapeutic agent Irrigation Jaw Label Laboratories Lead Legal patent Lesion Link Los Angeles Mandible Marketing Maxilla Measures Methods Minerals Modality Modeling Modification Mus Necrosis Nitrogen Operative Surgical Procedures Oral Oral cavity Oral mucous membrane structure Osteoporosis Outcome Pain Patients Pharmaceutical Preparations Phase Prevalence Prevention Prevention therapy Preventive Procedures Property Quality of life Reagent Reporting Research Risedronate Risk Rodent Model School Dentistry Series Side Site Skeletal system Small Business Technology Transfer Research Structure Surgeon Symptoms Tail Technology Testing Therapeutic Time Tissues Tooth Extraction Topical application Trauma Uncertainty Universities Veins Zoledronate base bisphosphonate bone data modeling design drug distribution experience fluorescence imaging fluorophore imaging probe in vivo innovation maxillofacial mouse model novel novel therapeutic intervention pre-clinical prevent programs public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Osteonecrosis of the jaw (ONJ) is a rare but severe oral complication, which is characterized by symptoms consisting painful bone exposure or fistulation that do not resolve over several months to years. It was initially described in patient treated with nitrogen-containing bisphosphonates (BPs), and was also found later in some patients taking other antiresorptive or antiangiogenic medications. In some cases, ablation surgery of necrotic oral and maxillofacial bones has been required, significantly affecting patients' life quality. Clinical reports have indicated that dental procedures markedly increase the risk of developing ONJ, thus causing uncertainty and apprehension among dental healthcare professionals and patients in recent years. "Drug holiday" has been recommended by American Association of Oral and Maxillofacial Surgeons (AAOMS) as a possible preventive measure for the patients. However, the FDA determined that there was no substantial data available to guide decisions regarding the initiation or duration of a drug holiday, which may partially be due to BPs' prolonged half-life in the skeletal system. In addition, because BPs have been marketed for nearly 15 years, a large number of patients have been treated with BPs and those patients who had received BPs but discontinued the therapy may retain the legacy BPs in their skeletal system for an extended period. Therefore, it may be essential to actively remove adsorbed BP from jawbone prior to dentoalveolar procedures in order to achieve more effective prevention. C.E. McKenna (University of Southern California, USC) and I. Nishimura (University of California Los Angeles, UCLA) recently demonstrated using fluorescently labeled BPs that one BP can displace another from hydroxyapatite modeling bone mineral. This suggests that a previously adsorbed pharmacologically active BP in bone could be displaced by a newly administered pharmacologically inactive BP. In this application, we propose this "competitive equilibrium"-based displacement of BPs as a novel preventive modality of bisphosphonate-related ONJ (BRONJ). We will test the hypothesis that a pre-adsorbed functional BP such as risedronate may be effectively displaced by a non-functional BP administered by intraoral injection to the jaw. As such, application of a non-functional BP to the site of dentoalveolar procedures such as tooth extraction should displace the functional BP locally and thus significantly reduce or abate the risk of developing BRONJ while preserving the benefit of skeletally adsorbed drug. In this Phase I STTR project, we will perform a proof- of-concept study in a mouse model and establish the drug distribution profile with local intraoral injection. Our program combines complementary strengths in ONJ mechanism (Nishimura, UCLA) with BP drug chemistry and biology (F.H. Ebetino, BioVinc LLC, C.E. McKenna, USC).

描述（由申请人提供）：颌骨坏死（ONJ）是一种罕见但严重的口腔并发症，其特征是疼痛性骨暴露或瘘管，这些症状在数月至数年内无法缓解。在接受含氮双膦酸盐（BP）治疗的患者中发现了这种情况，后来在一些服用其他抗吸收或抗血管生成药物的患者中也发现了这种情况。临床报告表明，牙科手术会显着增加患上颌面骨的风险，从而导致牙科医疗保健专业人员和患者近年来建议“药物假期”。美国口腔颌面外科医师协会（AAOMS）将其作为患者的一种可能的预防措施，但是 FDA 确定没有大量数据可以指导有关药物假期的开始或持续时间的决策，这可能部分是由于。由于BPs在骨骼系统中的半衰期较长，此外，由于BPs已上市近15年，大量患者接受了BPs治疗，而那些接受BPs但停止治疗的患者可能仍保留治疗效果。因此，在牙槽手术之前积极清除颌骨中吸附的 BP 可能非常重要，以实现更有效的预防。 C.E. McKenna（南加州大学，南加州大学）和 I. Nishimura（加州大学洛杉矶分校，加州大学洛杉矶分校）最近使用荧光标记的 BP 证明，一种 BP 可以从羟基磷灰石建模骨矿物质中取代另一种 BP，这表明先前吸附的具有药理活性的 BP。在本申请中，我们提出这种基于“竞争性平衡”的 BP 置换作为一种新型预防性方法。我们将测试以下假设：通过口腔内注射非功能性 BP 可以有效地替代预吸附的功能性 BP（例如利塞膦酸盐）。 - 拔牙等牙槽手术部位的功能性血压应取代局部功能性血压，从而显着降低或减轻患 BRONJ 的风险，同时保留骨骼的益处在这一阶段的 STTR 项目中，我们将在小鼠模型中进行概念验证研究，并通过局部口内注射建立药物分布曲线。我们的计划结合了 ONJ 机制（西村，加州大学洛杉矶分校）与 BP 的互补优势。药物化学和生物学（F.H. Ebetino、BioVinc LLC、C.E. McKenna、南加州大学）。