Evaluating the effect of injection protocols on intrathecal solute dispersion in non-human primates: an in vitro study using a cynomolgus cerebrospinal fluid system.

IF 5.9 1区 医学 Q1 NEUROSCIENCES
Goutham Kumar Reddy Burla, Dev Shrestha, Mayumi Bowen, Joshua D Horvath, Bryn A Martin
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引用次数: 0

Abstract

Background: Achieving effective drug delivery to the central nervous system (CNS) remains a challenge for treating neurological disorders. Intrathecal (IT) delivery, which involves direct injection into the cerebrospinal fluid (CSF), presents a promising strategy. Large animal studies are important to assess the safety and efficacy of most drugs and treatments and translate the data to humans. An understanding of the influence of IT injection parameters on solute distribution within the CNS is essential to optimize preclinical research, which would potentially help design human clinical studies.

Methods: A three-dimensional (3D) in vitro model of a cynomolgus monkey, based on MRI data, was developed to evaluate the impact of lumbar injection parameters on intrathecal solute dispersion. The parameters evaluated were (a) injection location, (b) bolus volume, (c) flush volume, (d) bolus rate, and (e) flush rate. To simulate the CSF flow within the subarachnoid space (SAS), an idealized CSF flow waveform with both cardiac and respiratory-induced components was input into the model. A solution of fluorescein drug surrogate tracer was administered in the lumbar region of the 3D in vitro model filled with deionized water. After injection of the tracer, the CSF system wide-solute dispersion was imaged using high-resolution cameras every thirty seconds for a duration of three hours. To ensure repeatability each injection protocol was repeated three times. For each protocol, the average spatial-temporal distribution over three hours post-injection, the area under the curve (AUC), and the percent injected dose (%ID) to extra-axial CSF (eaCSF) at three hours were determined.

Results: The changes to the lumbar injection parameters led to variations in solute distribution along the neuro-axis. Specifically, injection location showed the most impact, enhancing the delivery to the eaCSF up to + 10.5%ID (p = 0.0282) at three hours post-injection. Adding a post-injection flush of 1.5 ml at 1 ml/min increased the solute delivery to the eaCSF by + 6.5%ID (p = 0.0218), while the larger bolus volume resulted in a + 2.3%ID (p = 0.1910) increase. The bolus and flush rates analyzed had minimal, statistically non-significant effects.

Conclusion: These results predict the effects of lumbar injection parameters on solute distribution in the intrathecal space in NHPs. Specifically, the choice of injection location, flush, and bolus volume significantly improved solute delivery to eaCSF. The in vitro NHP CSF model and results offer a system to help predict and optimize IT delivery protocols for pre-clinical NHP studies.

评估注射方案对非人灵长类动物鞘内溶质分散的影响:使用犬脑脊液系统进行的体外研究。
背景:向中枢神经系统 (CNS) 有效给药仍是治疗神经系统疾病的一项挑战。将药物直接注入脑脊液(CSF)的鞘内给药是一种很有前景的策略。大型动物实验对于评估大多数药物和治疗方法的安全性和有效性以及将数据转化为人体数据非常重要。了解 IT 注射参数对溶质在中枢神经系统内分布的影响对于优化临床前研究至关重要,这可能有助于设计人体临床研究:方法:根据核磁共振成像数据,开发了一种犬科猴三维(3D)体外模型,以评估腰部注射参数对鞘内溶质分散的影响。评估参数包括:(a) 注射位置;(b) 注射量;(c) 冲洗量;(d) 注射速率;(e) 冲洗速率。为模拟蛛网膜下腔(SAS)内的 CSF 流,模型中输入了理想化的 CSF 流波形,其中包括心脏和呼吸引起的成分。在注入去离子水的三维体外模型腰部区域注入荧光素药物替代示踪剂溶液。注射示踪剂后,使用高分辨率照相机每隔 30 秒钟对 CSF 系统的宽绝对弥散进行成像,持续三小时。为确保重复性,每个注射方案重复三次。对每个方案都测定了注射后三小时内的平均时空分布、曲线下面积(AUC)和三小时后轴向外 CSF(eaCSF)的注射剂量百分比(%ID):结果:腰部注射参数的变化导致溶质沿神经轴分布的变化。具体来说,注射位置的影响最大,在注射后三小时,向轴外侧CSF的输送增加了+ 10.5%ID (p = 0.0282)。注射后以 1 毫升/分钟的速度冲洗 1.5 毫升,可使流向 eaCSF 的溶质增加 + 6.5%ID (p = 0.0218),而更大的栓剂量可使溶质增加 + 2.3%ID (p = 0.1910)。所分析的栓剂和冲洗率的影响极小,在统计学上无显著性:这些结果预测了腰部注射参数对非营利组织鞘内空间溶质分布的影响。结论:这些结果预测了腰部注射参数对溶质在NHP鞘内空间分布的影响。具体来说,注射位置、冲洗和栓剂量的选择能显著改善溶质向eaCSF的输送。体外 NHP CSF 模型和结果提供了一个系统,有助于预测和优化临床前 NHP 研究的 IT 输送方案。
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来源期刊
Fluids and Barriers of the CNS
Fluids and Barriers of the CNS Neuroscience-Developmental Neuroscience
CiteScore
10.70
自引率
8.20%
发文量
94
审稿时长
14 weeks
期刊介绍: "Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease. At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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