Extraocular Muscle (EOM) Responses to Bupivacaine Injection

布比卡因注射的眼外肌 (EOM) 反应

• 批准号: 7736517
• 负责人: Joel M Miller
• 金额: $ 59.03万
• 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/7736517
• 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; Randomized Controlled Clinical Trials; 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; 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（由申请人提供）：大多数现有的斜视治疗依赖于眼外肌代偿性损伤（EOMs）；我们正在开发一种替代方案，以可控的方式加强eom并改变其刚度和长度。动物肌内注射布比卡因（BUP）后，快速肌（如EOM）的肥厚是一致的结果。BUP是一种局部作用的肌毒素，可引起肌纤维变性、卫星细胞活化和肌纤维再生，并持续肥大。在球后麻醉过程中，无意中将BUP注射到人类EOM中会导致斜视的模式，模型显示这是由于肌肉作用场的收缩性显着增加，而影响相反场的僵硬度略有增加。我们也有初步的结果表明，肌肉再生的长度取决于眼睛在再生过程中的姿势。本项目旨在通过家兔的生物力学和组织学研究，以及斜视患者的临床、MR成像、肌力和模拟研究，探讨BUP注射后EOM的变化类型、量、持续性和机制。我们将BUP注射到正常的和实验性瘫痪的兔子眼肌中，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。我们将从组织学上评估肌纤维计数、大小和分离、结构和超微结构变化，包括瘢痕和纤维化。我们将改变注射量和浓度，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。这将扩展到垂直和斜肌以及双亲性疾病。我们将在注射前和注射后使用磁共振成像（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准、眼球运动、扫视速度和肌肉力量，并记录任何副作用或并发症。随着剂量、注射技术和安全性数据的可用性和标准化，我们将设计一项比较BUP注射和斜视手术治疗水平斜视的随机试验。BUP注射控制肌肉强化似乎准备提供一个强大的和有价值的斜视管理的新工具。在较短的长度上再生肌肉可以模仿手术切除的效果。长时间再生肌肉会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的肌肉大小变化和功能，都是实现这一目标的必要条件。BUP注射还有望治疗眼睑下垂和眼科以外的肌肉疾病。公共卫生相关性：注射局麻药布比卡因可增加肌肉的大小和强度，并改变肌肉的长度。我们将发展这一发现，作为斜视或斗鸡眼手术治疗的替代方法。这种方法的扩展为许多肌肉疾病的治疗带来了巨大的希望。