Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism

利培酮对骨重建和能量代谢影响的药理学

基本信息

批准号：
8430228
负责人：
Karen L. Houseknecht
金额：
$ 30.36万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-18 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8430228
关键词：
Accounting Acute Address Adolescent Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Adult Adverse effects Animals Antipsychotic Agents Behavior Disorders Binding Biology Bone Density Bone Marrow Bone Matrix Bone Resorption Bone remodeling Budgets Cells Child Chronic Clozapine Complex Coupling Data Development Diabetes Mellitus Dopamine Dopamine D2 Receptor Drug Exposure Drug Kinetics Endocrine Endocrine Glands Endocrinology Energy Metabolism Event Failure Fatty acid glycerol esters Fracture G-Protein-Coupled Receptors Generations Goals Health Policy Healthcare Histamine H1 Receptors Histamine Receptor Human Hypogonadism Hypothalamic structure In Vitro Incidence Insulin Interdisciplinary Study Label Mediating Medicine Mental disorders Metabolic Molecular Monitor Mus N-Methyl-D-Aspartate Receptors Neuraxis Neurosciences Non-Insulin-Dependent Diabetes Mellitus Obesity Osteoblasts Osteocalcin Osteoclasts Osteogenesis Output Patient Monitoring Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Plasma Prevention Production Prolactin Propranolol Public Health Publishing Receptor Signaling Reporting Research Risk Risperidone Schizophrenia Serotonin Signal Transduction Skeleton Sympathetic Nerve Block Sympathetic Nervous System Testing Time Weight Gain Work Workplace adiponectin adrenergic alpha-adrenergic receptor bisphosphonate bone bone cell bone health bone loss bone mass bone metabolism bone turnover disability drug metabolism improved in vivo innovation mineralization mouse model novel olanzapine osteoblast differentiation patient population prevent public health relevance quetiapine receptor receptor binding receptor function sex skeletal substantia spongiosa

项目摘要

DESCRIPTION (provided by applicant): Second generation anti-psychotics (SGAs) are widely prescribed to treat psychiatric disorders in adults and children and are among the 10 top selling medications world-wide. The pharmacology of SGAs is complex: they potently antagonize multiple G protein coupled receptors (GPCRs) including dopamine, serotonin, alpha- adrenergic and histamine receptors. Side effects of SGAs include increased incidence of obesity and type 2 diabetes among both acute and chronic users. Recent evidence indicates that SGAs are also associated with increased fracture risk and reduced bone mineral density; however the underlying molecular and pharmacological mechanisms leading to these severe endocrine side effects are unknown. Children and adolescents are the most susceptible to metabolic side effects, and in this proposal we hypothesize, that the skeleton is also vulnerable during the time of peak bone accrual. Thus the over-arching goal of this proposal is to elucidate the cellular/pharmacological mechanisms underlying SGA-induced bone loss, using the most widely prescribed, SGA, risperidone (RIS). Our novel central hypothesis is that RIS therapy is associated with significant bone loss, and this adverse side effect occurs via multiple mechanisms: 1) by directly interacting with bone cells and uncoupling bone remodeling; [2) via hyper-prolactinemia induced hypogonadism] and 3) by modulating the sympathetic nervous system output to bone. The goals of this project are to 1) determine whether SGAs have direct effects on osteoclast and osteoblast biology; 2) to examine the effect of RIS treatment in vivo on the skeletal-energy metabolism network, 3) determine if effects are mediated, at least in part by the sympathetic nervous system (SNS) and/or hypogonadism; and 4) to determine if detrimental effects of RIS on bone can be ameliorated with mechanism-directed co-therapy. To achieve these goals we will employ a pharmacologic approach to explore the functional consequence of specific receptor binding effects of RIS, and prolactin-sparing SGAs olanzapine and clozapine, using osteoblast and osteoclast culture in vitro, and in vivo by using established mouse models of RIS-induced bone loss. We will also explore whether ¿-blocker or bisphosphonate co-therapy can alter adverse effects of RIS on bone and energy metabolism. Finally, an important part of our strategy involves continuous monitoring of drug exposure (RIS and its active metabolite, 9-OH RIS) in plasma and bone marrow in order to gain understanding of the pharmacokinetic/pharmacodynamic relationships associated with adverse endocrine side effects of RIS therapy. These studies are both innovative and collaborative, capitalizing on the complementary strengths (pharmacology, drug metabolism, endocrinology, bone biology, diabetes, and neuroscience) of our interdisciplinary research team. Results of these novel mechanistic pharmacology studies may help inform public health policy concerning SGA prescribing and patient monitoring practices and may help inform strategies for prescribing co-therapies in order to minimize side effects in vulnerable patient populations.

描述（由适用提供）：第二代抗心理药物（SGA）被广泛规定，以治疗成人和儿童的精神疾病，并且是全球10种销量最高的药物之一。 SGA的药理学很复杂：它们可能拮抗多种G蛋白偶联受体（GPCR），包括多巴胺，5-羟色胺，α-肾上腺素和组胺受体。 SGA的副作用包括急性和慢性使用者中肥胖的发生率增加和2型糖尿病。最近的证据表明，SGA也与骨折风险增加和骨矿物质密度降低有关。但是，导致这些严重内分泌副作用的基本分子和药物机制尚不清楚。儿童和青少年最容易受到代谢副作用的影响，在我们假设的这一提案中，骨骼在峰值骨骼准确性时期也很脆弱。这是该提案的总体目标是阐明使用最广泛的SGA，Risperidone（RIS）使用最广泛的SGA诱导骨质流失的细胞/药理机制。我们新颖的中心假设是RIS治疗与明显的骨质流失有关，并且这种不利的副作用是通过多种机制发生的：1）通过直接与骨细胞相互作用并解开骨骼重塑； [2）通过过度乳酸诱导的性腺功能减退症]和3）通过调节交感神经系统输出到骨头。该项目的目标是1）确定SGA是否对成骨细胞和成骨细胞生物学有直接影响； 2）检查体内RIS治疗对骨骼 - 能源代谢网络的影响，3）确定是否介导了效应，至少部分是由交感神经系统（SNS）和/或降压体介导的； 4）为了确定RIS对骨骼的有害影响是否可以通过指导的共治疗来改善骨骼。为了实现这些目标，我们将采用药物方法来探索RIS的特定受体结合效应的功能后果，以及使用成骨细胞和骨质细胞培养的催乳素的SGAS Olanzapine和氯氮平，以及使用既定的RIS诱导的小鼠诱导的小鼠模型。我们还将探索� -Blocker或Bisphosphonate Co -Themapy是否可以改变RIS对骨骼和能量代谢的不利影响。最后，我们策略的重要部分是在血浆和骨髓中持续监测药物暴露（RIS及其活性代谢产物，9-OH RIS），以了解与RIS治疗的不良内分泌副作用相关的药代动力学/药物学关系。这些研究既具有创新性和协作性），并利用了我们跨学科研究团队优势的完整性（药理学，药物代谢，内分泌生物学，糖尿病和神经科学）。这些新颖的机械药理学研究的结果可能有助于告知有关SGA开处方和患者监测实践的公共卫生政策，并可能有助于为开处方的策略提供依据，以最大程度地减少脆弱患者人群的副作用。