PEDIATRIC PK/PD STUDY OF ORAL BACLOFEN FOR SPASTICITY ASSOCIATED WITH CP

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 巴氯芬是一种骨骼肌松弛剂，FDA批准用于治疗多发性硬化和脊髓损伤的成人痉挛。 巴氯芬是γ-氨基丁酸（GABA）的对氯苯基衍生物，主要在脊髓中与GABA受体结合，减少兴奋性神经递质的释放。巴氯芬对单突触和多突触通路具有突触前和突触后作用（Gracies，1997）。期望的临床效果是减弱短潜伏期和长潜伏期伸展反应以及放松肌肉痉挛。 巴氯芬已被证明可减轻成人的痉挛、疼痛性肌肉痉挛和阵挛，尽管数据有限且有些不一致（Chou et al 2004，Dario & Tomei 2004）。一些报告表明，巴氯芬可能对脊髓源性痉挛患者比脑源性痉挛患者更有效（Knutsson et al 1974）。 尽管口服巴氯芬已用于成人和儿童痉挛的治疗数十年，但关于巴氯芬在儿童中的药代动力学（PK）或药效学（PD）特性的数据非常少。因此，儿科指南（包括剂量范围、给药方案、剂量递增策略和预期副作用）是根据成人数据推断的，需要假设儿童的安全性和疗效与成人相当。此外，在治疗脑瘫（CP）儿童的医生中，起始剂量、最大剂量和剂量递增率的给药策略存在很大差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Baclofen is a skeletal muscle relaxant that is FDA approved for the treatment of spasticity in adults with multiple sclerosis and spinal cord injury. Baclofen, the p-chlorophenyl derivative of Gamma Amino Butyric acid (GABA), binds to GABA receptors, primarily in the spinal cord, where it reduces excitatory neurotransmitter release. Baclofen has both pre and post synaptic effects on monosynaptic and polysynaptic pathways (Gracies, 1997). The desired clinical effects are an attenuation of short and long latency stretch responses, and a relaxation of muscle spasms. Baclofen has been shown to reduce spasticity, painful muscle spasms and clonus in adults although data are limited and somewhat inconsistent (Chou et al 2004, Dario & Tomei 2004). Some reports suggest that baclofen may be more effective in patients with spasticity of spinal origin rather than cerebral origin (Knutsson et al 1974). Although oral baclofen has been used for several decades for the treatment of spasticity in adults and in children, there is very little data regarding the pharmacokinetic (PK) or pharmacodynamic (PD) properties of baclofen in children. Therefore, pediatric guidelines, including dose ranges, dosing schedules, dose escalation strategies and anticipated side effects are extrapolated from adult data and require an assumption that safety and efficacy in children is comparable to that in adults. Furthermore, there is wide variability in dosing strategies among practitioners who treat children with cerebral palsy (CP) with respect to starting doses, maximum doses and rates of dose escalation.