Skeletal Effects of Methylphenidate

哌甲酯对骨骼的影响

• 批准号: 9211356
• 负责人: David E Komatsu
• 金额: $ 32.6万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-02 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211356
• 关键词: Acute; Adolescent; Adult; Adverse drug effect; Adverse effects; Agreement; Alkaline Phosphatase; American; Anabolism; Animals; Attention deficit hyperactivity disorder; Attentional deficit; Biological Markers; Biomechanics; Body Weight; Bone Density; Bone Growth; Bone Mineral Contents; Catabolism; Cell Culture Techniques; Chronic; Clinical; Clinical Research; Clinical Trials; Collagen; Culture Media; Data; Densitometry; Diagnosis; Disease; Dose; Estrogens; Evaluation; Female; Fracture; Future; Gene Expression; Goals; Growth; Harvest; Health; Height; Immunohistochemistry; Impairment; Laboratories; Leptin; Measures; Mediating; Mental disorders; Metabolism; Methylphenidate; Molecular; Observational Study; Osteoblasts; Patients; Pharmaceutical Preparations; Physiologic calcification; Protocols documentation; Rattus; Recovery; Regimen; Reporting; Research; Research Personnel; Research Project Grants; Risk; Ritalin; Serum; Site; Skeletal Development; Symptoms; Testing; Testosterone; Withholding Treatment; Work; bone; bone quality; bone strength; clinically relevant; crosslink; density; design; dosage; experimental study; improved; male; microCT; psychostimulant; public health relevance; reduce symptoms; response; sex; skeletal; spine bone structure

DESCRIPTION (provided by applicant): The overall goal of this research project is to determine if and how chronic methylphenidate (MP) treatment is detrimental to skeletal development, as well as evaluate the ability of altered dosing regimens to mitigate any adverse skeletal effects. MP is the most widely prescribed drug for treating attention deficit hyperactivit disorder (ADHD), with ~5% of US adolescents currently taking it. While generally well-tolerated and effective for alleviating the symptoms of ADHD, MP administration is associated with growth suppression of ~1cm/year. Consistent with these clinical observations, studies in our laboratory demonstrated that treatment of adolescent rats with MP resulted in decreased bone size, bone mineral density, bone mineral content, and biomechanical integrity in appendicular, but not axial skeletal sites. Although these adverse effects were ameliorated within 5 weeks of treatment cessation, these data suggest that during the course of MP treatment, patients may be at an increased risk for bone fractures. Given the large and growing number of US adolescents taking MP, a thorough evaluation of the potential adverse effects of this drug on skeletal development is warranted. As well, alternative dosing regimens that may be able to mitigate these effects, while still providing symptomatic relief, need to be tested. As such, this proposal seeks to furthe elucidate the effects of MP on skeletal development by testing the hypothesis that MP administration results in acute impairment of appendicular skeletal development in adolescent rats. We will test this hypothesis by the following specific aims: 1) Assess skeletal development in male and female rats treated with MP at 2 clinically relevant dosages, as well as in vehicle treated and pair-fed controls; 2) Determine if alternative dosing protocols (i.e., 5 days on/2 days off and 3 weeks on/1 week off) can mitigate the adverse effects of MP on skeletal development; and 3) Evaluate the direct and indirect effects of MP on primary rat osteoblast viability, proliferation, differentiation, and activity. These studies will provide a comprehensive understanding of the precise effects of MP on skeletal development, evaluate the ability of alternative dosing protocols to mitigate the adverse of MP on skeletal development, and begin to elucidate the mechanism underlying these effects. In turn, these data will aid clinicians in the design of future clinical trials, as well as make more informed prescribing decisions to protect the skeletal health of patients with ADHD.

描述（由申请人提供）：该研究项目的总体目标是确定慢性哌醋甲酯（MP）治疗是否对骨骼发育有害，并评估改变剂量方案的能力减轻任何不良骨骼效应。 MP是治疗注意力缺陷超级活力障碍（ADHD）的最广泛规定的药物，目前约有5％的美国青少年服用。虽然通常良好的耐受性且有效缓解多动症的症状，但MP给药却与〜1cm/年的生长抑制有关。与这些临床观察一致，我们的实验室研究表明，对青少年大鼠的MP治疗导致骨骼尺寸降低，骨矿物质密度，骨矿物质含量和生物力学完整性，而不是轴向骨骼部位。尽管这些不良反应在治疗停止后的5周内得到了改善，但这些数据表明，在MP治疗过程中，患者可能会增加骨折的风险。鉴于美国青少年越来越多地接受国会议员，因此有必要对该药物对骨骼发育的潜在不利影响进行彻底评估。同样，需要对这些作用缓解这些影响的替代剂量方案，同时仍需要进行症状缓解。因此，该提案试图通过检验以下假设来阐明MP对骨骼发育的影响：MP给药会导致青少年大鼠阑尾骨骼发育的急性损害。我们将通过以下特定目的检验这一假设：1）评估在2种临床相关剂量以及媒介物处理和配对的对照中，用MP处理的男性和雌性大鼠的骨骼发育； 2）确定替代给药方案是否（即5天/2天） 休假和3周休假）可以减轻MP对骨骼发育的不利影响； 3）评估MP对原代大鼠成骨细胞活力，增殖，分化和活性的直接和间接影响。这些研究将对MP对骨骼发育的确切影响提供全面的理解，评估替代剂量方案减轻MP对骨骼发育的不良反应的能力，并开始阐明这些作用的基本机制。反过来，这些数据将帮助临床医生 设计未来的临床试验，并做出更明智的开处方决定，以保护多动症患者的骨骼健康。