For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) minimal diffusion in the brain severely limits drug distribution after direct drug administration in to brain parenchyma. We systemically investigated convection, molecular transport with bulk flow of fluid, to enhance the distribution of large and small molecules, indium111-transferrin (In111-Tf; MW 80,000) and C14-sucrose (MW 359), by maintaining a pressure gradient during interstitial infusion to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing greater than or equal to 1% of infusate concentration increased linearly with the infusion volume (Vi) for In111- Tf (Vd/Vi=6.1) and C14-sucrose (Vd/Vi=14.1). 24 hr after infusion, the distribution of In111-Tf increased, became more homogeneous, and penetration into gray matter occurred. By using convection to supplement simple diffusion, greatly enhanced distribution of large and small molecules can be achieved in the brain while achieving drug exposure orders of magnitude greater than systemic exposure. Convection-enhances distribution was shown to be an effective technique to homogeneously deliver large and small molecules in the gray matter of rats and non- human primates. the infusion of molecular selectively toxic to certain subsets of neurons is now being investigated as a potential new therapeutic strategy for Parkinson's disease and for seizures. Continuous perfusion of most of the cerebral hemisphere of monkeys was achieved for several days with an implanted controllable pump.
| Lonser, Russell R; Warren, Katherine E; Butman, John A et al. (2007) Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 107:190-7 |
| Morrison, Paul F; Lonser, Russell R; Oldfield, Edward H (2007) Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J Neurosurg 107:74-83 |
| Szerlip, Nicholas J; Fox, Elizabeth; Manosca, Frances et al. (2007) Pancreatoblastoma metastases to the brain. Case illustration. J Neurosurg 106:169 |
| Lonser, R R; Schiffman, R; Robison, R A et al. (2007) Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease. Neurology 68:254-61 |
| Walbridge, Stuart; Murad, Gregory J A; Heiss, John D et al. (2006) Technique for enhanced accuracy and reliability in non-human primate stereotaxy. J Neurosci Methods 156:310-3 |
| Murad, Gregory J A; Walbridge, Stuart; Morrison, Paul F et al. (2006) Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to pseudomonas exotoxin. Clin Cancer Res 12:3145-51 |
| Tender, Gabriel C; Walbridge, Stuart; Olah, Zoltan et al. (2005) Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation. J Neurosurg 102:522-5 |
| Heiss, John D; Walbridge, Stuart; Morrison, Paul et al. (2005) Local distribution and toxicity of prolonged hippocampal infusion of muscimol. J Neurosurg 103:1035-45 |
| Lonser, Russell R; Walbridge, Stuart; Murray, Gary J et al. (2005) Convection perfusion of glucocerebrosidase for neuronopathic Gaucher's disease. Ann Neurol 57:542-8 |
| Croteau, David; Walbridge, Stuart; Morrison, Paul F et al. (2005) Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer. J Neurosurg 102:90-7 |
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