Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Xiaotong Fan, Brian D. Nelson, Yi Ai, David K. Stiles, Don M. Gash, Peter A. Hardy, Zhiming Zhang

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Object Assessing the safety and feasibility of chronic delivery of compounds to the brain using convection-enhanced delivery (CED) is important for the further development of this important therapeutic technology. The objective of this study was to follow and model the distribution of a compound delivered by CED into the putamen of rhesus monkeys. Methods The authors sequentially implanted catheters into 4 sites spanning the left and right putamen in each of 6 rhesus monkeys. The catheters were connected to implanted pumps, which were programmed to deliver a 5-mM solution of the MRI contrast agent Gd-DTPA at 0.1 μl/minute for 7 days and 0.3 μl/minute for an additional 7 days. The animals were followed for 28 days per implant cycle during which they were periodically examined with MRI. Results All animals survived the 4 surgeries with no deficits in behavior. Compared with acute infusion, the volume of distribution (Vd) increased 2-fold with 7 days of chronic infusion. Increasing the flow rate 3-fold over the next week increased the Vd an additional 3-fold. Following withdrawal of the compound, the half-life of Gd-DTPA in the brain was estimated as 3.1 days based on first-order pharmacokinetics. Histological assessment of the brain showed minimal tissue damage limited to the insertion site. Conclusions These results demonstrate several important features in the development of a chronically implanted pump and catheter system: 1) the ability to place catheters accurately in a predetermined target; 2) the ability to deliver compounds in a chronic fashion to the putamen; and 3) the use of MRI and MR visible tracers to follow the evolution of the infusion volume over time.

Original languageEnglish
Pages (from-to)1569-1577
Number of pages9
JournalJournal of Neurosurgery
Volume123
Issue number6
DOIs
StatePublished - Dec 2015

Bibliographical note

Publisher Copyright:
© AANS, 2015.

Keywords

  • Convection-enhanced delivery
  • Magnetic resonance imaging
  • Parkinson disease
  • Rhesus macaques

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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