首页> 外文期刊>Toxicologic pathology >Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF in rhesus monkeys.
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Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF in rhesus monkeys.

机译:重组蛋氨酸人胶质细胞源性神经营养因子(r-metHuGDNF)在恒河猴中的六个月连续腹腔内输注毒性研究。

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摘要

Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson's disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6-9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 microg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 microl/day flow rate) for 6 months; a subset of animals (2-3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 microg/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 microg/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-microg/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.
机译:重组人神经胶质细胞系衍生的神经营养因子(r-metHuGDNF)是一种有效的神经元生长和存活因子,已被认为可用于临床治疗帕金森氏病(PD)。在这里,我们介绍了在恒河猴中进行的为期6个月的毒理学研究的结果,以支持对r-metHuGDNF进行慢性腹膜内输注以进行PD的临床评估。通过连续单侧腹腔内输注(150微升/天流量),以0(载体),15、30或100微克/天r-metHuGDNF处理猴子(6-9 /性别/组),持续6个月;一小部分动物(2-3只/性别/组)经历了随后的3个月无治疗恢复期。值得注意的观察包括以100微克/天减少食物消耗和体重,以及延髓和/或以30和100微克/天覆盖各种脊髓节段的脑膜增厚。此外,在100微克/天组中的4只猴子中观察到多灶性小脑浦肯野细胞损失(伴随分子层萎缩,在某些情况下还伴随着颗粒细胞损失)。在先前评估r-metHuGDNF的非临床研究中未观察到此小脑发现。受感染的动物数量很少,因此无法得出有关小脑病变发病机理的确切结论,但数据支持与r-metHuGDNF治疗有关。

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