Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques.
OBJECTIVE
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.
Department of Neurosurgery, Xuan Wu Hospital, Capital Medical University, Beijing, China;|Department of Anatomy & Neurobiology, College of Medicine.
Xiaotong
X
Fan
Medtronic Inc., Minneapolis, Minnesota.
Brian D
BD
Nelson
Department of Anatomy & Neurobiology, College of Medicine.
Yi
Y
Ai
Medtronic Inc., Minneapolis, Minnesota.
David K
DK
Stiles
Department of Anatomy & Neurobiology, College of Medicine.
Don M
DM
Gash
Magnetic Resonance Imaging and Spectroscopy Center, and.|Department of Radiology, Chandler Medical Center, University of Kentucky, Lexington, Kentucky; and.
Peter A
PA
Hardy
Department of Anatomy & Neurobiology, College of Medicine.
Zhiming
Z
Zhang
D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018481:Convection; D016503:Drug Delivery Systems; D005260:Female; D019786:Gadolinium DTPA / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015918:Infusion Pumps, Implantable; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D011699:Putamen / Q000378:metabolism*
D003287:Contrast Media; D019786:Gadolinium DTPA
BBB = blood-brain barrier; CED = convection-enhanced delivery; NHP = nonhuman primate; Parkinson disease; convection-enhanced delivery; magnetic resonance imaging; rhesus macaques; siRNA - small interfering RNA