CHRONIC INTERSTITIAL INFUSION OF PROTEIN TO PRIMATE BRAIN - DETERMINATION OF DRUG DISTRIBUTION AND CLEARANCE WITH SINGLE-PHOTON EMISSION COMPUTERIZED-TOMOGRAPHY IMAGING

High-flow interstitial infusion into the brain, which uses bulk fluid flow to achieve a relatively homogeneous-drug distribution in the extr acellular space of the brain, has the potential to perfuse large volum es of brain. The authors report reproducible long-term delivery of In- 111-diethylenetriamine pentaacetic acid-apontransferrin (In-111-DTPA-T f) (molecular mass 81 kD) to Macaca mulatta brain and monitoring with single-photon emission computerized tomography (SPECT). The In-111-DTP A-Tf was infused at 1.9 mu l/minute over 87 hours into the frontal por tion of the centrum semiovale using a telemetry-controlled fully impla nted pump. On Days 1, 3, 4, 8, 11, and 15 after beginning the infusion , planar and SPECT scans of In-111-DTPA-Tf were obtained. Spread of pr otein in the brain ranged from 2 to 3 cm and infusion volumes ranged f rom 3.9 to 6.7 cm(3). Perfusion of over one-third of the white matter of the infused hemisphere was achieved. From brain SPECT images of Tc- 99m-hexamethylpropyleneamine oxime, which was administered intravenous ly before each In-111 scan, the authors also found that blood perfusio n in the infused region was reduced by less than 5% relative to corres ponding noninfused regions. Histological, examination at 30 days revea led only mild gliosis limited to the area immediately surrounding the needle tract. These findings indicate that long-term interstitial brai n infusion is effective for the delivery of drugs on a multicentimeter scale In the primate brain. The results also indicate that it should be possible to perfuse targeted regions of the brain for extended inte rvals to investigate the potential utility of neurotrophic factors, an titumor agents, and other materials for the treatment of central nervo us system disorders.