Extraocular Muscle (EOM) Responses to Bupivacaine Injection

布比卡因注射的眼外肌 (EOM) 反应

• 批准号: 7915323
• 负责人: Joel M Miller
• 金额: $ 61.12万
• 依托单位: SMITH-KETTLEWELL EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915323
• 关键词: Adult; Adverse effects; Affect; Agonist; Anesthesia procedures; Anesthetics; Animal Experiments; Animals; Bilateral; Biomechanics; Blepharoptosis; Botox; Bupivacaine; Cell Nucleus; Cells; Characteristics; Cicatrix; Clinical; Clinical Research; Connective Tissue; Contralateral; Data; Denervation; Dimensions; Disease; Dose; Edema; Effectiveness; Elasticity; Electric Stimulation; Electromyography; Electrons; Enrollment; Esotropia; Event; Excision; Eye; Eye Movements; Fiber; Fibrosis; Generations; Goals; Growth Factor; Histologic; Hour; Human; Hypertrophy; Impairment; In Situ; In Vitro; Inflammatory; Injection of therapeutic agent; Intramuscular Injections; Laboratory Study; Lead; Left; Length; Light; Local Anesthetics; Longevity; Magnetic Resonance Imaging; Maintenance; Measurement; Measures; Methods; Microscopic; Modeling; Molecular; Monitor; Muscle; Muscle Fibers; Muscle function; Myofibrils; Myopathy; Natural regeneration; New Zealand; Ocular orbit; Operative Surgical Procedures; Ophthalmology; Oryctolagus cuniculus; Outcome; Outcome Measure; Paralysed; Paresis; Patients; Pattern; Pharmaceutical Preparations; Photography; Plant Resins; Positioning Attribute; Posture; Process; Rattus; Recovery; Reporting; Saccades; Safety; Saline; Sarcomeres; Secondary to; Site; Strabismus; Stretching; Surgical sutures; Techniques; Testing; Time; Tissue Preservation; Tissues; cell motility; clinical application; design; dosage; experience; gaze; human subject; inclusion criteria; interest; muscle degeneration; muscle hypertrophy; nerve supply; orbit muscle; pilot trial; prevent; public health relevance; randomized trial; repaired; response; satellite cell; secondary outcome; simulation; superior rectus muscle; tool; trial comparing; volunteer

Description (provided by applicant): Most existing treatments for strabismus rely on compensatory impairment of extraocular muscles (EOMs); we are developing an alternative to strengthen EOMs and alter their stiffnesses and lengths in controllable ways. Hypertrophy of fast muscle, such as EOM, is a consistent consequence of intramuscular injection of bupivacaine (BUP) in animals. BUP is a locally acting myotoxin that causes muscle fiber degeneration, satellite cell activation, and muscle fiber regeneration, continuing to hypertrophy. Inadvertent injection of BUP into human EOM during retrobulbar anesthesia causes a pattern of strabismus that modeling suggests is due to significantly increased contractility in the muscle's field of action and slightly increased stiffness affecting the opposite field. We also have preliminary results suggesting that muscles are regenerated at a length determined by eye posture during regeneration. This project aims to explore the types, amount, persistence, and mechanisms of changes in EOM after BUP injection by means of biomechanical and histological studies in rabbits, and by clinical, MR imaging, muscle force, and simulation studies in strabismus patients. We will inject BUP into normal and experimentally paralyzed rabbit eye muscles, with some eyes held in predetermined postures during regeneration. We will measure changes in muscle dimensions, elasticity, and contractile force. We will histologically assess muscle fiber counts, sizes and separations, and structural and ultrastructural changes, including scarring and fibrosis. We will vary injected volume and concentration to determine the dosage of BUP needed to safely produce beneficial effects. We have begun a pilot trial of BUP injection into EOMs of adult strabismus patients with very encouraging results in comitant horizontal cases. This will be extended to vertical and oblique muscles and to paretic disorders. We will use magnetic resonance imaging (MRI) before and at intervals after injection to verify injection sites and measure changes in muscle size. We will measure and compare binocular alignment, ocular motility, saccadic velocities, and muscle forces before and after injection, and note any side effects or complications. As data on dosage, injection technique, and safety become available and standardized, we will design a randomized trial comparing BUP injection and strabismus surgery for horizontal strabismus. Controlled muscle strengthening by BUP injection appears poised to provide a powerful and valuable new tool for strabismus management. Regenerating muscles at reduced lengths would mimic the effects of surgical resection. Regenerating muscles at increased lengths would produce effects unobtainable with surgery. Fully understanding the basic muscle changes in animal experiments and accurately documenting muscle size changes and function in patients with various disorders are both essential to this end. BUP injection also holds promise for treatment of eyelid ptosis and for muscle disorders beyond ophthalmology. PUBLIC HEALTH RELEVANCE: Injection of the local anesthetic bupivacaine can increase the size and strength, and alter the lengths of muscles. We will develop this finding as an alternative to surgical treatment for strabismus, or crossed eyes. Extension of this approach holds great promise for treatment of many muscle disorders.

描述(申请人提供)：大多数现有的斜视治疗依赖于眼外肌的代偿性损伤(EOMS)；我们正在开发一种替代方案，以可控的方式加强EOMS并改变其僵硬和长度。快速肌肉肥大，如EOM，是动物肌肉内注射布比卡因(BUP)的一贯结果。BUP是一种局部作用的肌毒素，可导致肌肉纤维变性、卫星细胞激活和肌肉纤维再生，继续肥大。在球后麻醉期间，无意中将BUP注射到人的EOM中，导致了斜视的模式，建模表明，这是由于肌肉活动区域的收缩能力显着增加，而影响对侧场的僵硬程度略有增加。我们也有初步的结果表明，肌肉在再生过程中的长度由眼睛的姿势决定。本项目旨在通过生物力学和组织学研究，以及斜视患者的临床、磁共振成像、肌力和模拟研究，探讨BUP注射后EOM的类型、数量、持续时间和机制。我们将把BUP注射到正常和实验性瘫痪的兔眼肌肉中，在再生过程中，一些眼睛保持预定的姿势。我们将测量肌肉尺寸、弹性和收缩力的变化。我们将从组织学角度评估肌肉纤维的数量、大小和分离，以及结构和超微结构的变化，包括瘢痕形成和纤维化。我们将改变注射的体积和浓度，以确定安全产生有益效果所需的BUP剂量。我们已经开始在成人斜视患者的EOMS中注射BUP的试点试验，在伴随的水平病例中取得了非常令人鼓舞的结果。这将扩展到垂直肌和斜肌，以及偏瘫疾病。我们将在注射前和注射后每隔一段时间使用磁共振成像(MRI)来验证注射部位并测量肌肉大小的变化。我们将测量和比较注射前后的双眼对齐、眼球运动、眼球跳动速度和肌力，并记录任何副作用或并发症。随着剂量、注射技术和安全性方面的数据变得可用和标准化，我们将设计一项随机试验，比较BUP注射和斜视手术治疗水平斜视。通过注射BUP进行受控肌肉强化似乎有望为斜视治疗提供一种强大而有价值的新工具。在较短的长度上再生肌肉将模拟手术切除的效果。增加长度的肌肉再生将产生手术无法达到的效果。充分了解动物实验中肌肉的基本变化，准确记录各种疾病患者肌肉大小和功能的变化，都是实现这一目标的关键。BUP注射也有望治疗眼睑下垂和眼科以外的肌肉疾病。与公众健康相关：注射局部麻醉剂布比卡因可以增加肌肉的大小和力量，并改变肌肉的长度。我们将把这一发现发展为斜视或对眼手术治疗的替代方案。这一方法的推广为许多肌肉疾病的治疗带来了巨大的希望。